TW201542196A - Ophthalmic formulation - Google Patents

Abstract

The present invention provides an ophthalmic composition in which (a) a geranyl geranyl acetone (GGA) and (b) a retinal disease therapeutic agent (but excluding GGA) are coexisted, thereby suppressing a side effect of conjunctival injection and/or corneal problem resulted from (b) the retinal disease therapeutic agent (but excluding GGA). In addition, the present ophthalmic composition suppresses white turbidity of the ophthalmic composition and the adsorption of GGA on a container, and improves thermal stubility and/or photo stability.

Description

Ophthalmic preparation

The present invention relates to ophthalmic preparations.

A therapeutic agent for retinopathy such as glaucoma, known as a prostaglandin agent (prostaglandin F2 α derivative), a sympatholytic agent, a sympathetic nerve stimulating agent, a parasympathetic stimulating agent, a carbonic anhydrase inhibitor, a ROCK inhibitor And other medicines.

Such agents mainly improve retinopathy by reducing intraocular pressure to inhibit the progression of retinal nerve cell damage.

Representative side effects of therapeutic agents for retinopathy such as glaucoma include corneal damage such as corneal inflammation and erosion, eye irritation, conjunctival hyperemia, and the like (Non-Patent Document 1, Non-Patent Document 2 Abstract, page 311, right column, lines 1 to 5, Page 312, left column, line 14 to 18, etc.).

Since retinopathy such as glaucoma is a progressive chronic disease, the therapeutic agent is usually used for a long period of time. Therefore, it is desirable to treat such retinopathy therapeutic agents as much as possible to suppress their side effects.

Here, Patent Document 1 discloses a specific derivative of prostaglandin A, B, D, E, or F, inhibits local side effects in a prior glaucoma therapeutic agent, and also lowers intraocular pressure to exert glaucoma treatment. effect.

Meanwhile, Patent Document 2 discloses that in a glaucoma therapeutic agent containing a β-blocking agent which reduces the production of an anterior chamber fluid and a carbachol which increases the efflux of the anterior chamber fluid, the anionic mucin-like polymerization is further formulated. The substance and the fine cation exchange resin can reduce the side effects of the beta blocking agent and carbachol.

[Previous Technical Literature]

[Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 8-109132

[Patent Document 2] Japanese Patent Laid-Open No. 5-194471

[Non-patent literature]

[Non-Patent Document 1] Ophthalmology Assessment Article 11, Glaucoma Drug Treatment Handbook 2012, 133, 152, 153, 163, 171-173, 177

[Non-Patent Document 2] Arch Ophthalmol 126: 309-315, 2008

An object of the present invention is to provide an ophthalmic preparation containing a therapeutic agent for retinopathy, which is a preparation having few side effects.

In order to solve the above problems, the inventors of the present invention have repeatedly studied and found that a therapeutic agent for retinopathy is combined with geranylgeranylacetone (hereinafter sometimes referred to as "GGA"). The conjunctival hyperemia and/or corneal damage that inhibits the side effects of the therapeutic agent for retinopathy.

GGA, for example, a mixture of 5 E , 9 E , 13 E geranylgeranylacetone and 5 Z , 9 E , 13 E geranylgeranylacetone in a weight ratio of 3:2, which has been treated with teprenone (teprenone) (made by Eisai) is sold under the trade name. Several reports have also indicated the results of animal experiments on the effects of resveratrol on oral administration by intraperitoneal administration and intraperitoneal administration (JP-A-2009-507770, "The American Journal of Pathology, Vol. 178, No. 3, March 2011, 1080-1090", "Investigative Ophthalmology & Visual Science, May 2003, Vol. 44, No. 5, 1982-1992", "The Journal of Neuroscience, March 2," 2005, 25(9), 2396-2404", "Molecular Vision, 2007, 13, 1601-1607", "Neuroscience Letters, 462, 2009, 281-285").

Among them, the present inventors have found that GAA in an ophthalmic preparation is a component which is significantly adsorbed on an ophthalmic container more than other agents. For example, vitamin A and vitamin E which are known to be easily adsorbed on a container are more likely to have more container adsorption amount than those in ophthalmic preparation components. Meanwhile, the present inventors have also found that GGA is inhibited from being adsorbed on an ophthalmic container by using GGA and a retinopathy therapeutic agent other than GGA.

In addition, the ophthalmic preparations are required to reduce the turbidity as much as possible. The present inventors have also found that by using GGA and a therapeutic agent for retinopathy other than GGA, the solubility of GGA is improved, so that the GGA-containing ophthalmic preparation is further improved. clarify.

Meanwhile, the present inventors have also found that GGA has improved heat and light stability by using GGA in combination with retinopathy therapeutic agents other than GGA.

Therefore, the present invention has been completed in accordance with the above findings, and provides the following ophthalmic preparation.

Item 1. An ophthalmic preparation comprising (a) geranylgeranylacetone, and (b) a therapeutic agent for retinopathy (however, other than geranylgeranylacetone).

The ophthalmic preparation according to the first aspect, wherein the retinopathy therapeutic agent (other than the geranylgeranylacetone) is selected from the group consisting of a prostaglandin agent and a sympatholytic agent. , sympathetic nerve stimulating agent, parasympathetic nerve stimulating agent, carbonic anhydrase inhibitor, ROCK inhibitor, calcium antagonist, EP2 promoter, adenosine A2a receptor agonist, VEGF aptamer, and VEGF inhibition One or more of the groups formed by the agents.

Item 3. The ophthalmic preparation according to Item 1 or 2, which is a prophylactic, ameliorating, or therapeutic agent for retinopathy.

Item 4. The ophthalmic preparation according to Item 3, wherein the retinopathy is selected from the group consisting of glaucoma, retinitis pigmentosa, senile macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular degeneration, hypertension Retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tear, retinal hole, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented venous retinal choroidal atrophy, convoluted choroidal retina Atrophy, no pulse Collateral malformation, crystal retinopathy, white spot retinitis, cone dystrophy, central halo-like choroidal atrophy, Doyne honeycomb retinal dystrophy, yolk-like macular dystrophy, macular cystic edema Lesions, occult macular dystrophy, Stargardt disease, retinolysis, central serous chorioretinopathy, spinocerebellar atrophy type 7, familial exudative vitreoretinopathy, heavy cone Enhanced S-cone syndrome, retinal vascular pattern, chromosomal dominant optic atrophy, chromosomal dominant choroidal drusen, acute banded retinal outer lesion, tumor-induced retinopathy, One or more lesions in the group of photodamage and ischemic retinopathy.

Item 3. The ophthalmic preparation according to any one of items 1 to 4, which is an eye drop, an intraocular injection, an eye ointment, an eye wash, a contact lens assembly liquid, a contact lens solution, and a transplant. Corneal extraction of ocular tissue preservation agent, intraoperative infusion solution, sustained release intraocular implant, or sustained release contact lens preparation.

The ophthalmic preparation according to any one of the items 1 to 5, which is an aqueous composition or an oily composition.

The ophthalmic preparation according to any one of items 1 to 6, which is in the form of a liquid, a fluid, a gel, or a semisolid.

The ophthalmic preparation according to any one of the items 1 to 7, wherein the therapeutic agent for retinopathy (other than the geranylgeranylacetone) causes conjunctival hyperemia and/or Or the property of causing damage to the cornea is inhibited.

The ophthalmic preparation according to any one of the items 1 to 8, wherein the adsorption of the geranylgeranylacetone to the container is inhibited.

Item 10. The ophthalmic preparation according to any one of items 1 to 9, wherein the white turbidity is inhibited.

The ophthalmic preparation according to any one of items 1 to 10, wherein the geranylgeranylacetone has an improved heat and/or light stability.

The ophthalmic preparation according to any one of the items 1 to 11, wherein the ointment-based geranylacetone is contained in an amount of 0.00001 to 90% by weight based on the total amount of the preparation.

The ophthalmic preparation according to any one of items 1 to 12, which contains 0.00001 to 90% by weight of a therapeutic agent for retinopathy relative to the total amount of the preparation (however, it is a geranylgeranyl group) Other than acetone).

The ophthalmic preparation according to any one of the items 1 to 13, wherein the ophthalmic preparation is contained in an amount of 0.0001 to 100,000 parts by weight based on 1 part by weight of the geranylgeranylacetone (but , other than geranyl geranylacetone).

Item 15. The ophthalmic preparation according to any one of items 1 to 14, which is a geranylgeranylacetone, and a therapeutic agent for retinopathy (however, other than geranylgeranylacetone) A compound agent contained in the same composition, or a geranylgeranylacetone is contained in a combined preparation of individual compositions.

Item 16. A method by which the ophthalmic group is used In the preparation, (a) geranylgeranylacetone and (b) retinopathy therapeutic agent (however, other than geranylgeranylacetone) are coexistent, and the ophthalmic composition is inhibited (b) The effect of conjunctival hyperemia and/or corneal damage caused by a therapeutic agent for retinopathy (except for those other than geranylgeranylacetone).

Item 17. A method for treating (a) geranylgeranylacetone and (b) retinopathy therapeutic agent (other than geranylgeranylacetone) by the ophthalmic composition Coexistence, while inhibiting the white turbidity of the ophthalmic composition.

Item 18. A method for treating (a) geranylgeranylacetone and (b) retinopathy therapeutic agent (but, other than geranylgeranylacetone), in an ophthalmic composition Coexistence, while inhibiting the adsorption of geranylgeranyl-based acetone in the container.

Item 19. A method for treating (a) geranylgeranylacetone and (b) retinopathy therapeutic agent (other than geranylgeranylacetone) by an ophthalmic composition Coexistence enhances the heat and/or light stability of geranylgeranylacetone.

GGA improves survival by directly acting on retinal nerve cells, protecting cell damage, inhibiting cell death. At the same time, by inducing or promoting cell axon elongation, the function of the cells is enhanced, and the damaged retinal cells are regenerated. Therefore, GGA is an agent that can completely treat retinopathy.

On the other hand, treatment agents for retinopathy other than GGA, by descending Low intraocular pressure inhibits the progression of retinal nerve cell damage.

Therefore, the ophthalmic preparation of the present invention protects various retinal cells from degeneration, damage, or death by various actions, and exhibits remarkable effects in preventing, improving, or treating various retinopathy. That is, since the ophthalmic preparation of the present invention is used in combination with a therapeutic agent for retinopathy other than GGA, the prevention, improvement, or therapeutic effect of retinopathy is remarkably enhanced.

Meanwhile, according to the present invention, conjunctival hyperemia and/or corneal damage which are side effects of a therapeutic agent for retinopathy other than GGA are suppressed by using GGA in combination. In the case of inhibiting conjunctival hyperemia, there is also a situation in which recovery from conjunctival hyperemia is promoted. Moreover, corneal epithelial damage is known to be related to eye irritation, so GGA should also suppress eye irritation caused by retinopathy therapeutic agents other than GGA in the eye. On the other hand, GGA itself is a drug which is widely used and safely determined. Therefore, the ophthalmic preparation of the present invention is an agent excellent in safety. The retinopathy is a progressive chronic disease, and therefore the general therapeutic agent is long-term use. According to the present invention, an ophthalmic preparation which can be used for a long period of time in the prevention, improvement, or treatment of retinopathy is provided.

At the same time, the ophthalmic preparation of the present invention can significantly suppress the GGA adsorption to an ophthalmic container (hereinafter sometimes referred to as "container") and the stability of GGA to heat and light, thereby maintaining the amount of GGA in the preparation. At the same time, the selection of the container material is expanded due to the excellent light stability, and the management of transportation and storage is easy due to the excellent thermal stability.

Moreover, the ophthalmic preparation of the present invention contains even poorly soluble The GGA of water also inhibits its turbidity to a low value. Meanwhile, in the ophthalmic preparation of the present invention, the therapeutic agent for retinopathy other than GGA is used in combination to suppress the temporal turbidity caused by storage, especially the temporal white turbidity caused by storage at a low temperature.

In the ophthalmic preparation, it is required to minimize turbidity from the viewpoint of uniform administration and the likeness of the patient, and the ophthalmic preparation of the present invention is excellent in turbidity. At the same time, the ophthalmic preparation of the present invention is used to expand the design range of the preparation for dissolving GGA, and the management of transportation and storage in winter and cold regions is also easy.

Fig. 1 is a view showing the action of protecting cells from hypoxia and low glucose-induced ischemic cell death via GGA.

Fig. 2 is a graph showing the effect of inducing axonal elongation via GGA in rat RGC.

Fig. 3 is a graph showing that GGA inhibits conjunctival hyperemia by a prostaglandin-based agent.

Fig. 4 is a graph showing that GGA inhibits conjunctival hyperemia by a ROCK inhibitor.

Fig. 5 is a graph showing the cytotoxicity of GGA-inhibiting beta blocking agents and carbonic anhydrase inhibitors.

Hereinafter, the present invention will be described in detail.

The ophthalmic preparation of the present invention contains (a) GGA, and (b) GGA. A therapeutic agent for retinopathy other than the active ingredient.

Geranyl geranyl acetone ((a) component) (1) Types of geometric isomers

There are eight geometric isomers in GGA. Specifically, there are eight kinds of the following: (5 E , 9 E , 13 E )-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5 E , 9 E , 13 E GGA) (all-trans isomer), (5 Z , 9 E , 13 E )-6,10,14,18-tetramethyl-5,9,13,17 - nineteentetradecen-2-one (5 Z , 9 E , 13 E GGA) (5Z monocis isomer), (5 Z , 9 Z , 13 E )-6,10,14,18- Tetramethyl-5,9,13,17-non-tetradecen-2-one (5 Z , 9 Z , 13 E GGA) (13E SLR isomer), (5 Z , 9 Z , 13 Z )-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5 Z ,9 Z ,13 Z GGA) (trans-isomer) ,(5 E ,9 Z ,13 E )-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5 E , 9 Z , 13 E GGA) (9Z monocis isomer), (5 E , 9 Z , 13 Z )-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecene-2 -ketone (5 E , 9 Z , 13 Z GGA) (5E mono-trans isomer), (5 E , 9 E , 13 Z )-6,10,14,18-tetramethyl-5,9,13 , 17-undecyltetraen-2-one (5 E , 9 E , 13 Z GGA) (13Z monocis isomer), and (5 Z , 9 E , 13 Z )-6,10,14 , 18-Tetramethyl-5,9,13,17-non-tetradecen-2-one (5 Z , 9 E , 13 Z GGA) (9E monotrans isomer).

Further, there are cases where a 5Z monocis isomer, a 9Z single cis isomer, and a 13Z single cis isomer are combined and described as a single cis isomer.

In the present invention, the type of GGA is not limited, and one type may be used alone or in combination of two or more types.

Among them, a GGA geometric isomer mixture containing 80% by weight or more of all-trans isomers and all-trans isomers (especially, containing all-trans isomers) a single cis isomer (particularly, a 5Z monocis isomer) and a total trans isomer ratio of 80% by weight or more of the mixture), a single cis isomer, and a monocis isomer 80% by weight or more of the GGA geometric isomer mixture (in particular, containing a single cis isomer (particularly, 5Z monocis isomer) and all-trans isomer, and a single cis isomer A mixture of 80% by weight or more of the ratio) and a mixture of general geometric isomers containing the all-trans isomer and the 5Z monocis isomer in a weight ratio of 3:2 is preferred.

In the GGA geometric isomer mixture containing 80% by weight or more of the total trans isomer, the ratio of the total trans isomer is 80% by weight or more, and more preferably 82% by weight or more, and 84% by weight or more. Preferably, 86% by weight or more is more preferably 88% by weight or more, more preferably 90% by weight or more, more preferably 92% by weight or more, more preferably 94% by weight or more, and even more preferably 96% by weight or more. More preferably 98% by weight or more. If it is in the above range, it shows a remarkable effect in prevention, improvement, or treatment of retinopathy.

Meanwhile, in the GGA geometric isomer mixture containing 80% by weight or more of the monocis isomer, the ratio of the monocis isomer is 80% by weight or more, and more preferably 82% by weight or more, and 84% by weight or more. More preferably, it is more preferably 86% by weight or more, more preferably 88% by weight or more, and 90% by weight. More preferably, it is more preferably 92% by weight or more, more preferably 94% by weight or more, still more preferably 96% by weight or more, and still more preferably 98% by weight or more. If it is in the above range, it shows a remarkable effect in prevention, improvement, or treatment of retinopathy.

At the same time, a mixture of general geometric isomers containing a full trans isomer and a 5Z monocis isomer in a weight ratio of 3:2 is preferred in terms of ease.

(2) Method for producing GGA geometric isomer <all trans isomer>

5 E , 9 E , 13 E GGA (all-trans isomer) is a compound represented by the following structural formula.

All-trans isomers are commercially available, for example, from Rionlon.

At the same time, by using commercially available teprenone (Wei Cai, Wako Pure Chemical Co., Ltd., Jinyangtang Co., Ltd.), a silicone layer such as n-hexane:ethyl acetate=9:1 can be used as the mobile phase. The separation was carried out by separation from the 5Z monocis isomer. Separation of the 5Z monocis isomer from the commercially available teprenone with the all-trans isomer can also be entrusted to, for example, Kobe Natural Chemicals.

Meanwhile, the all-trans isomer can also be synthesized, for example, by the method described in Bull. Korean Chem. Soc., 2009, Vol. 30, No. 9, 215-217. In the same document, for example, the method shown in the following synthesis scheme is also described.

Specifically, in the above reaction formula, the geranyl-based linalool 1 is mixed with the compound 2 and aluminum isopropoxide, and the mixture is gradually heated to 130 ° C to carry out a reaction. After the end of the reaction, after removing the residue of Compound 2, the reaction mixture was diluted with 5% sodium carbonate, and the residue was quenched. Thereby, the all-trans isomer is obtained. Thereafter, dichloromethane is used as an elution solution to purify the all-trans isomer by gelatin chromatography or the like.

<single cis isomer>

5 Z , 9 E , 13 E GGA (5Z monocis isomer) is a compound represented by the following structural formula.

The 5Z monocis isomer can be isolated from commercially available teprenone.

<Other>

Other GGA geometric isomers can be made by the prior art by reference to the above methods.

a mixture of all-trans isomers and 5Z mono-cis isomers, and containing a mixture of all-trans isomers of 80% by weight or more, by adding all-trans isomorphism to commercially available teprenone Structure made. At the same time, 5Z single cis isomer Mixtures with all-trans isomers and containing more than 80% by weight of the 5Z monocis isomer can be prepared by adding 5Z monocis isomer to commercially available teprenone.

Retinopathy treatment agent other than (a) component ((b) component)

The therapeutic agent for retinopathy other than GGA (hereinafter sometimes referred to as "the therapeutic agent for retinopathy") is not particularly limited. In particular, a retinopathy therapeutic agent having side effects such as conjunctival hyperemia and/or corneal damage is more preferable in that the effect of the present invention is remarkably exhibited. The therapeutic agent for retinopathy other than GGA is preferably exemplified by a prostaglandin agent (prostaglandin F2 α derivative), a sympathetic blocker (sympathetic beta blocker, and a sympathetic β 1 selective blocker). , sympathetic α 1 blocking agent, sympathetic α 2 blocking agent, sympathetic α β blocking agent), sympathetic stimulation agent (non-selective stimulating agent, α 2 stimulating agent), parasympathetic stimulating agent (choline) A chemokine, a cholinesterase inhibitor, a carbonic anhydrase inhibitor, a ROCK inhibitor, a calcium antagonist, an EP2 promoter, an adenosine A2a receptor stimulating agent, a VEGF aptamer, a VEGF inhibitor, and the like. In particular, a prostaglandin-based agent, a sympathetic beta blocker, a ROCK inhibitor (Rho kinase inhibitor), and a carbonic anhydrase inhibitor are preferred.

<Prostaglandin agent>

The prostaglandin-based therapeutic agent for retinopathy is not limited thereto, and examples thereof include: latanoprost, terfuprost. Prostaglandin-based agents such as (travoprost), tafluprost, and bimatoprost (prostamide-based agents, prostanoid-based agents); unoprostone A prostaglandin-based agent such as isopropyl unoprostone. These are prostaglandin F2 alpha derivatives. Among them, prostaglandin-based agents are preferred, and latanoprost is particularly preferred.

<sympathetic blocker>

The sympathetic nerve blocking agent is not limited, and may, for example, be a timolol maleate, a colloidal timolol, a carteolol hydrochloride, or a colloidal Carter. Selective beta blocker; beta 1 selective beta blocker such as betaxolol hydrochloride; alpha beta blocker such as levobunolol hydrochloride, nipradilol Broken agent; α 1 blocking agent such as bunazosin hydrochloride. Among them, a non-selective β blocking agent is preferred, and thiacin is particularly preferred.

<ROCK inhibitor (Rho kinase inhibitor)>

Rho kinase has two isoforms of Rho kinase α/ROK α/ROCK2 and Rho kinase β/ROK β/ROCK1. In the present invention, a ROCK inhibitor (hereinafter sometimes referred to as "ROCK inhibitor") may be one of those which inhibit ROCK2, one which inhibits ROCK1, and one of which inhibits both. At the same time, it can also activate other serine/threonines that are activated by the activation of Rho. Enzyme inhibiting agent.

The ROCK inhibitor is not limited in itself, and may, for example, be fasudil hydrochloride (Wako Pure Chemical Co., Ltd.), Y-27632 (Wako Pure Chemical Co., Ltd.), K-115 (Hinghe Co., Ltd.), SNJ- 1656 (Qianshou Pharmaceutical Co., Ltd.), AR-12286 (Aerie Pharmaceuticals), INS-117548 (Inspire Pharmaceuticals), and the like. Among them, fasudil hydrochloride is preferred.

<Carbonic anhydrase inhibitor (carbonic anhydrase inhibitor)>

The carbonic anhydrase inhibitor is not limited in itself, and examples thereof include acetazolamide, dorzolamide hydrochloride, and brinzolamide. Among them, Kangshumu hydrochloride is preferred.

Other, sympathetic nerve stimulating agents, for example, adrenal hormone, hydrogen tartrate tartrate, dipivefrine hydrochloride, brimonidine tartrate, etc.; parasympathetic stimulant, for example For example, pilocarpine hydrochloride, distigmine, etc.; calcium antagonists, such as: lomerizine hydrochloride; EP2 accelerator, for example For example: DE-117, etc.; adenine nucleoside A2a receptor stimulating agent, for example, OPA-6566, etc.; VEGF aptamer, may be exemplified by: pegaptanib sodium; VEGF inhibition The agent can be exemplified by, for example, ranibizumab, bevacizumab, and the like.

a group selected from the group consisting of a prostaglandin agent, a sympathetic beta blocker, a ROCK inhibitor, and a carbonic anhydrase inhibitor The therapeutic agent for omental lesions may be used alone or in combination of two or more. When two or more types are combined, the same system of agents may be used, for example, a combination of two or more prostaglandin-based drugs, or a different system of agents, such as a prostaglandin-based agent and a sympathetic β-blocking agent.

A combination of GGA and a therapeutic agent for retinopathy selected from the group consisting of a prostaglandin agent, a sympathetic beta blocker, a ROCK inhibitor, and a carbonic anhydrase inhibitor may, for example, be a GGA and a prostaglandin system. Combination of agents (eg, a combination of GGA and latanoprost, a combination of GGA and Tefprostin, a combination of GGA and tafluprost, a combination of GGA and bimatoprost) a combination of prostaglandin agents; a combination of GGA and a prostaglandin agent such as a combination of GGA and unoprostone isopropyl ester; a combination of GGA and a sympatholytic agent (eg, GGA and maleic acid) Combination of timolol, combination of GGA and colloidal timolol, combination of GGA and cartoterol hydrochloride, combination of GGA and non-selective beta blocking agent such as GGA and colloidal Carterol; GGA and hydrochloric acid Combination of GGA and β 1 selective β blocker such as combination of Betshulu; GGA and combination of Glycine hydrochloride, GGA and eptidolide, etc. Combination); combination of GGA and fasudil hydrochloride, GGA and Y-27 Combination of 632, combination of GGA and K-115, combination of GGA and SNJ-1656, combination of GGA and AR-12286, combination of GGA and ROCK inhibitor such as GGA and INS-117548; A combination of GGA and oxazolamide, a combination of GGA and konsop hydrochloride, a combination of GGA and a carbonic anhydrase inhibitor such as a combination of GGA and Aishu pressure.

At the same time, for example, a combination of GGA with latanoprost and thiaxanthine maleate, a combination of GGA with latanoprost and colloidal thizone, GGA and travoprost and Combination of thiophene succinate, combination of GGA with Teflon and colloidal timolol, combination of GGA with prostaglandin agents and sympathetic beta blockers; GGA and cis-butene Combination of timolol and hydrazide hydrochloride, combination of GGA and colloidal timolol and chlorhexidine hydrochloride, GGA and sympathetic beta blocker and carbonic anhydrase inhibitor Combination, etc.

preparation

The form of the ophthalmic preparation is not particularly limited, and may be, for example, any form such as a liquid, a fluid, a gel, a semi-solid, or a solid. At the same time, it also includes a liquid, a fluid, a gel, a semi-solid, or a solid by modulation at the time of use. The semi-solid state refers to, for example, an ointment, and has a form of plasticity deformed by application of pressure.

The type of ophthalmic preparation is not particularly limited. For example, eye drops (including eye-dropping items when the contact lens is assembled), eye wash, contact lens assembly liquid, contact lens liquid (cleaning liquid, preservation liquid, disinfectant, multi-function maintenance liquid, packaging preservation liquid) , transplanting the cornea, etc. Weaving preservative, infusion during surgery, eye ointment (water-soluble ointment, oil-soluble ointment), intraocular injection (such as intravitreal injection), sustained-release intraocular implant, and sustained-release contact lens preparation, etc. . Among them, an eye drop, an intraocular injection, an eye ointment, and an eye wash are preferred from the point of excellent transferability to the lesion, and an eye drop is more preferable.

Furthermore, the ophthalmic preparation may be an aqueous composition (the base or carrier contained therein is mainly aqueous or hydrophilic) or an oily composition (the base or carrier is mainly oily or hydrophobic) .

The content of water in the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the preparation. Moreover, the base or carrier may also contain only water.

The content of water in the oily composition is preferably 50% by weight or less, more preferably 30% by weight or less, and still more preferably 20% by weight or less based on the total amount of the preparation.

Modulation methods for ophthalmic preparations are generally well known. It can be prepared by mixing GGA, a pharmaceutically acceptable base or carrier, an optional pharmaceutically acceptable ophthalmic preparation additive, and other active ingredients (physiologically active ingredients other than GGA or pharmacologically active ingredients).

<base or carrier>

The base or carrier may, for example, be water; an aqueous solvent such as a polar solvent; a polyhydric alcohol; a vegetable oil; an oily base. The base or carrier of the intraocular injection may, for example, be distilled water for injection or physiological saline.

The base or the carrier may be used singly or in combination of two or more kinds.

<additive>

The additive may, for example, be a surfactant, a fragrance or a cooling agent, a preservative, a bactericide or an antibacterial agent, a pH adjuster, an isotonic agent, a chelating agent, a buffering agent, a stabilizer, an antioxidant, and a thickener. Wait. The intraocular injection may also contain a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent, a stabilizer, and a preservative.

The additives may be used singly or in combination of two or more kinds.

Specific examples of the additive can be exemplified as follows.

Examples of the surfactant include polyethylene oxide (hereinafter sometimes referred to as "POE")-polypropylene oxide (hereinafter sometimes referred to as "POP") block copolymer (e.g., Poloxamer-407, Poloxamer-235, Poloxamer-188), POE-POP block copolymer adduct of ethylenediamine (such as Poloxamine), POE sorbitan fatty acid ester (such as polysorbate 20, polysorbate) Alcohol ester 60, polysorbate 80 (TO-10, etc.), POE hydrogenated castor oil (such as POE (60) hydrogenated castor oil (HCO-60, etc.)), POE castor oil, POE alkyl ether (such as poly ring Ethylene oxide (9) lauryl ether, polyethylene oxide (20) polypropylene oxide (4) hexadecyl ether), and polyoxyl stearate Ionic surfactant; glycine type amphoteric surfactant (such as alkyldiaminoethylglycine, alkyl polyaminoethylglycine), and betaine type amphoteric surfactant (such as laurel An amphoteric surfactant such as dimethylaminoacetic acid betaine, imidazolium betaine; and alkyl quaternary ammonium salts (such as benzalkonium) A cationic surfactant such as chloride) or benzethonium chloride.

Furthermore, the numbers in parentheses indicate the addition of moles.

Examples of the fragrance or the cooling agent may, for example, camphor, borneol, terpenes (which may be any of the d isomer, l isomer or dl isomer), mint water, eucalyptus Oil, citrus oil, anethole, eugenol, geraniol, menthol, limonene, peppermint oil, peppermint oil, and essential oils such as rose oil.

Examples of the preservative, bactericide or antibacterial agent are exemplified by: polidronium chloride, alkyldiamine ethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, chlorine Benzyl ethoxylated ammonium, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraben, ethyl paraben, p-hydroxybenzene Propyl formate, butyl paraben, oxyquinoline, phenylethyl alcohol, benzyl alcohol, biguanide compounds (specifically, such as polyhexamethylene biguanide or its hydrochloride), and Gurokiru (manufactured by Rhodia Co., Ltd.) )Wait.

Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, and phosphoric acid.

Examples of the isotonic agent may, for example, be sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate or sulfuric acid. Magnesium, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, and propylene glycol.

Examples of the chelating agent can be exemplified by ascorbic acid and edetic acid Sodium, sodium edetate, and citric acid.

Examples of the buffering agent include, for example, a phosphate buffer; a citric acid buffer such as citric acid or sodium citrate; an acetic acid buffer such as acetic acid, potassium acetate or sodium acetate; sodium hydrogencarbonate or sodium carbonate; Carbonic acid buffer; boric acid buffer such as boric acid or borax; amino ethanesulfonic acid, aspartic acid and its salts (potassium salt, etc.), amino acid buffer such as ε-aminocaproic acid, and the like.

Among them, it is preferred to adjust the pH by using a phosphate buffer, and thus, the GGA is inhibited from adsorbing on the container wall, thereby further suppressing the decrease in the GGA content in the ophthalmic preparation. At the same time, the white turbidity at the time of cryopreservation can be more suppressed, and the effect of suppressing GGA adsorption on the contact lens and the stability of heat and light can be better.

The phosphate buffers may be used singly or in combination of two or more kinds.

The phosphate buffering agent is not particularly limited, and examples thereof include phosphoric acid; disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and phosphoric acid alkali such as tripotassium phosphate. Metal salt; calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, mono-magnesium phosphate, di-magnesium phosphate (magnesium hydrogen phosphate), tri-phosphoric acid alkaline earth metal salt; diammonium phosphate, ammonium dihydrogen phosphate, etc. Ammonium phosphate and the like. The phosphate buffer may be either an acid anhydride or a hydrate.

In particular, it is preferred to use at least one selected from the group consisting of phosphoric acid and an alkali metal phosphate, and at least one selected from the group consisting of phosphoric acid and sodium phosphate.

A preferred combination of the phosphate buffers may, for example, be a combination of phosphoric acid and disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate, and phosphoric acid and disodium hydrogen phosphate. And a combination of sodium dihydrogen phosphate, a combination of phosphoric acid and disodium hydrogen phosphate and trisodium phosphate, a combination of phosphoric acid with sodium dihydrogen phosphate and trisodium phosphate, a combination of disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate. Combination of phosphoric acid and disodium hydrogen phosphate, combination of phosphoric acid and sodium dihydrogen phosphate, combination of phosphoric acid and trisodium phosphate, combination of disodium hydrogen phosphate and sodium dihydrogen phosphate, combination of disodium hydrogen phosphate and trisodium phosphate, phosphoric acid A combination of sodium dihydrogen and trisodium phosphate.

Among them, a combination of phosphoric acid with disodium hydrogen phosphate and sodium dihydrogen phosphate, a combination of phosphoric acid and disodium hydrogen phosphate, a combination of phosphoric acid and sodium dihydrogen phosphate, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is preferred. The combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is preferred.

The content of the phosphate buffer is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and still more preferably 0.05% by weight or more, based on the total amount of the preparation. In the above range, the effect of GGA stabilization by addition of a phosphate buffer, the effect of suppressing low-temperature white turbidity, and the effect of inhibiting GGA adsorption on a container wall and a contact lens can be sufficiently obtained.

Meanwhile, the content of the phosphate buffer in the ophthalmic preparation is converted to an acid anhydride, preferably 10% by weight or less, more preferably 7% by weight or less, more preferably 5% by weight or less, and 3% by weight or less, based on the total amount of the preparation. Better yet. In the above range, less irritation to the eyes.

The content of the phosphate buffer is converted to an acid anhydride, and may be, for example, about 0.001 to 10% by weight, about 0.001 to 7% by weight, about 0.001 to 5% by weight, about 0.001 to 3% by weight, and about 0.005 to the total amount of the preparation. 10% by weight, about 0.005 to 7% by weight, about 0.005 to 5% by weight, About 0.005 to 3% by weight, about 0.01 to 10% by weight, about 0.01 to 7% by weight, about 0.01 to 5% by weight, about 0.01 to 3% by weight, about 0.05 to 10% by weight, about 0.05 to 7% by weight, about 0.05 to 5% by weight, about 0.05 to 3% by weight.

Meanwhile, the content of the phosphate buffer is preferably 0.0005 parts by weight or more, more preferably 0.001 part by weight or more, more preferably 0.005 part by weight or more, and still more preferably 0.01 part by weight or more, based on 1 part by weight of GGA. good. In the above range, the effect of GGA stabilization by addition of a phosphate buffer, the effect of suppressing low-temperature white turbidity, and the effect of inhibiting GGA adsorption on a container wall and a contact lens can be sufficiently obtained.

Meanwhile, the content of the phosphate buffer is converted to an acid anhydride, preferably 5,000 parts by weight or less, more preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, and still more preferably 200 parts by weight or less, based on 1 part by weight of GGA. good. In the above range, less irritation to the eyes.

The content of the phosphate buffer is converted to an acid anhydride, and may be, for example, about 0.0005 to 5000 parts by weight, about 0.0005 to 1000 parts by weight, about 0.0005 to 500 parts by weight, or about 0.0005 to 200 parts by weight, based on 1 part by weight of the GGA. About 0.001 to 5000 parts by weight, about 0.001 to 1000 parts by weight, about 0.001 to 500 parts by weight, about 0.001 to 200 parts by weight, about 0.005 to 5000 parts by weight, about 0.005 to 1000 parts by weight, about 0.005 to 500 parts by weight, or about 0.005 to 200 parts by weight, about 0.01 to 5000 parts by weight, about 0.01 to 1000 parts by weight, about 0.01 to 500 parts by weight, and about 0.01 to 200 parts by weight.

The preparation of the present invention is a combination of two or more dosage forms In the case of a composition containing GGA, a phosphate buffer is preferred. In this case, the content of the above phosphate buffer is in the amount of the composition containing GGA.

Examples of the stabilizers include, for example, trometamol, sodium formaldehyde sulfoxylate (carrageenan), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, and glycerol monostearate. Wait.

Examples of the antioxidant include ascorbic acid, ascorbic acid derivatives (disascorbic acid-2-disodium sulfate, sodium ascorbate, magnesium ascorbyl-2-phosphate, sodium ascorbyl-2-phosphate, etc.), sodium hydrogen sulfite, sodium sulfite, sulfur A water-soluble antioxidant such as sodium sulfate.

The ophthalmic preparation may further contain a fat-soluble antioxidant. Thus, the ophthalmic preparation is inhibited from adsorbing on the container wall, and the content of the GGA in the composition is further suppressed from decreasing. At the same time, it inhibits the adsorption of GGA on contact lenses, and improves the stability of GGA to heat and light.

Examples of the fat-soluble antioxidant may, for example, be butyl hydroxytoluene (BHT), butyl phenol such as butyl hydroxyanisole (BHA); n-dihydroguaiac acid (NDGA); ascorbyl palmitate , ascorbyl stearate, ascorbyl phosphate, ascorbyl phosphate, ascorbyl triphosphate, ascorbyl phosphate, ascorbate; α-tocopherol, β-tocopherol, γ-tocopherol, Tocopherols such as δ-tocopherol; tocopherol derivatives such as tocopheryl acetate, tocopherol nicotinic acid ester, tocopheryl succinate; ethyl gallate, propyl gallate, no Gallic acid ester of octyl octanoate, lauryl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; soybean oil, rapeseed Vegetable oils such as oil, olive oil, and sesame oil; carotenoids such as lutein and astaxanthin; Anthocyanins; polyphenols such as catechins, tannins, curcumin; retinol, retinol esters (retinyl acetate, retinyl propionate, retinyl butyrate, Retinyl octanoate, retinyl laurate, retinyl stearate, retinyl myristate, retinyl oleate, retinyl linolenate, linoleic acid retinoic acid Alcohol ester, retinyl palmitate, etc.), retinal, retinal, (retinal acetate, retinyl propionate, retinyl palmitate, etc.), retinoic acid, retinal Acid esters (methyl retinoic acid, ethyl retinoate, retinyl retinoic acid ester, tocopheryl retinoic acid ester, etc.), dehydrogen retinol, dehydroretinal, dehydrogenated retinoic acid, Provitamin A (α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, echinenone) Etc.), vitamin A and other vitamin A; CoQ10 and so on. Such compounds are commercially available.

Among them, butyl group-containing phenol, NDGA, ascorbate, tocopherol, tocopherol derivative, gallic acid ester, propyl gallate, and 3-butyl-4-hydroxyquinolin-2-one Vegetable oil and vitamin A are preferred. Among them, butyl-containing phenol, tocopherol, tocopherol derivative, vegetable oil, vitamin A are preferred, and butyl-containing phenol, vegetable oil, retinol or retinol ester is preferred, BHT, BHA, Sesame oil and retinyl palmitate are even better.

The fat-soluble antioxidant may be used singly or in combination of two or more kinds.

The content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, more preferably 0.0001% by weight or more, and still more preferably 0.0005% by weight or more, based on the total amount of the preparation. In the above range, sufficient fat solubility can be obtained by adding The antioxidant suppresses the effect of GGA adsorption on the container wall (the effect of suppressing the decrease in the GGA content), suppresses the effect of GGA adsorption on the contact lens, and improves the effect of GGA on heat and light stability.

Meanwhile, the content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 10% by weight or less, more preferably 5% by weight or less, more preferably 2% by weight or less, and still more preferably 1% by weight or less, based on the total amount of the preparation. good. In the above range, less irritation to the eyes.

The content of the fat-soluble antioxidant in the ophthalmic preparation may be, for example, about 0.00001 to 10% by weight, about 0.00001 to 5% by weight, about 0.00001 to 2% by weight, or about 0.00001 to 1% by weight, based on the total amount of the preparation. About 0.00005 to 10% by weight, about 0.00005 to 5% by weight, about 0.00005 to 2% by weight, about 0.00005 to 1% by weight, about 0.0001 to 10% by weight, about 0.0001 to 5% by weight, about 0.0001 to 2% by weight, about 0.0001 to 1% by weight, about 0.0005 to 10% by weight, about 0.0005 to 5% by weight, about 0.0005 to 2% by weight, and about 0.0005 to 1% by weight.

Meanwhile, the content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 0.0001 part by weight or more, more preferably 0.001 part by weight or more, more preferably 0.005 part by weight or more, and more preferably 0.01 part by weight or more based on 1 part by weight of GGA. Better yet. In the above range, the effect of suppressing the adsorption of GGA on the container wall by the addition of the fat-soluble antioxidant (the effect of suppressing the decrease in the GGA content), the effect of suppressing the adsorption of GGA on the contact lens, and the improvement of the heat of the GGA can be sufficiently obtained. And the effect of the stability of light.

Meanwhile, the content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 100 parts by weight or less based on 1 part by weight of GGA, and 50 parts by weight or less. More preferably, it is more preferably 10 parts by weight or less, and still more preferably 5 parts by weight or less. In the above range, less irritation to the eyes.

The content of the fat-soluble antioxidant in the ophthalmic preparation may be, for example, about 0.0001 to 100 parts by weight, about 0.0001 to 50 parts by weight, about 0.0001 to 10 parts by weight, and about 0.0001 to 5 parts by weight based on 1 part by weight of the GGA. Parts, about 0.001 to 100 parts by weight, about 0.001 to 50 parts by weight, about 0.001 to 10 parts by weight, about 0.001 to 5 parts by weight, about 0.005 to 100 parts by weight, about 0.005 to 50 parts by weight, about 0.005 to 10 parts by weight About 0.005 to 5 parts by weight, about 0.01 to 100 parts by weight, about 0.01 to 50 parts by weight, about 0.01 to 10 parts by weight, and about 0.01 to 5 parts by weight.

When the preparation of the present invention is a combination of two or more dosage forms, it is preferred to contain a fat-soluble antioxidant in the composition containing GGA. In this case, the content of the above fat-soluble antioxidant, that is, the amount in the composition containing GGA.

Examples of the thickener may be guar gum, hydroxypropyl guar, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose. Cellulose-based polymer compound such as sodium, gum arabic, tragacanth, tricyanidin, agar, alginic acid, α-cyclodextrin, dextrin, dextran, heparin, heparin, heparin Sulfuric acid, acesulfame heparin sulfate, hyaluronic acid, hyaluronate (sodium salt, etc.), sodium chondroitin, starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbus a polyethylene-based polymer compound such as an alcohol, a polyvinylpyrrolidone, a polyvinyl alcohol or a polyvinyl methacrylate, an alkali metal salt of a polyacrylic acid (a sodium salt or a potassium salt), or an amine salt of a polyacrylic acid ( single Carboxyvinyl polymer such as ethanolamine salt, diethanolamine salt, triethanolamine salt, etc., ammonium polyacrylate, casein, gelatin, collagen, pectin, elastin, neural amine, liquid paraffin, C Alcohol, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.), alginate (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine.

<Other pharmacologically active ingredients or physiologically active ingredients>

At the same time, in the ophthalmic preparation, the prophylactically active ingredient or the physiologically active ingredient other than the component of the prevention, improvement, or treatment of the retinopathy may be formulated. These pharmacologically active ingredients or physiologically active ingredients may be used singly or in combination of two or more kinds.

Examples of the pharmacologically active ingredient and the physiologically active ingredient may, for example, be a neurotrophic factor, a hyperemia-eliminating component, an eye muscle regulating agent component, an anti-inflammatory agent component or an astringent pharmaceutical component, an antihistamine pharmaceutical component or an antiallergic pharmaceutical component, A vitamin, an amino acid, an antibacterial agent or a bactericidal ingredient, a saccharide, a polymer compound, a cellulose or a derivative thereof, and a local anesthetic agent. Specific examples of such agents can be enumerated below.

Neurotrophic factors: NGF: Nerve growth factor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) .

Meanwhile, since the serum contains a nutrient factor including a neurotrophic factor, serum taken by the patient can also be added as a preparation for the patient.

Congestion-eliminating components: for example: α-adrenergic stimulating agents, such as: adrenaline, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, hydrochloric acid Naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, hydrogen epinephrine tartrate, and naphazoline nitrate. These may be any of the d isomer, the l isomer or the dl isomer.

Ocular muscle regulating agent component: for example, a cholinesterase inhibitor having an active center similar to acetylcholine, such as neostigmine methylsulfate, tropicamide, herenei, And atropine sulfate, and the like.

Anti-inflammatory agent or astringent agent: for example: zinc sulfate, zinc lactate, allantoin, ε-aminocaproic acid, indometacin, chlorinated lysozyme, silver nitrate, pranoprofen , sodium sulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, diclofenac sodium, bromfenac sodium, berberine chloride, and berberine sulfate.

Antihistamine pharmaceutical ingredient or anti-allergic agent component: such as: acitazanolast, diphenhydramine or its hydrochloride salt, chlorpheniramine maleate , ketotifen fumarate, levocabastine or its hydrochloride, amlexanox, ibudilast, tazarzide (amzanox) Salt of tazanolast), tranilast, oxatomide, suplatast or tosilate, sodium cromoglicic acid, and Pyrimisol potassium or the like.

Vitamins: for example: retinyl acetate, retinyl palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate , cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopheryl acetate, tocopheryl nicotinic acid ester, tocopheryl succinate, calcium citrate tocopherol, and ubiquinone derivatives Things and so on.

Amino acids: for example: aminoethyl sulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate Mixture, sodium glutamate, magnesium glutamate, ε-aminocaproic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, and cartilage Sodium sulfate and the like. These may be any of the d isomer, the l isomer or the dl isomer.

Antibacterial or bactericidal ingredients: for example: alkyl polyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sodium sulfamethoxazole, sulfonamide Isoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisoxazole sodium, sulfisomidine sodium, ofloxacin, norfloxacin, levofloxacin , lomefloxacin hydrochloride (lomefloxacin hydrochloride), and aciclovir (aciclovir).

Sugars: for example: monosaccharides, disaccharides, such as: glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.

Macromolecular compounds: for example: alginic acid, sodium alginate, dextrin, polydextrose, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (complete or partially saponified), polyvinylpyrrolidone, carboxyvinyl A polymer, a polyethylene glycol, a pharmaceutically acceptable salt thereof, and the like.

Cellulose or a derivative thereof: for example: ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose Sodium, carboxyethyl cellulose, nitrocellulose, and the like.

Local anesthetic agent components: for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, and the like.

Sustained release intraocular implant

Meanwhile, as for the ophthalmic preparation, a sustained release intraocular implant can be exemplified. Various methods of modulation are known for sustained release intraocular implants. For example, a matrix preparation prepared by mixing a therapeutic agent for retinopathy other than GGA and/or GGA with a carrier containing a high molecular substance, and a core of a therapeutic agent for retinopathy other than GGA and/or GGA may be used as a polymer film. In the preparation of the coating, a capsule preparation of a retinopathy therapeutic agent other than GGA and/or GGA is enclosed in a microcapsule formed of a high molecular substance.

The polymer is not particularly limited as long as it is a polymer for use in a sustained-release intraocular implant, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxypropylmethyl. Cellulose phthalate, pullulan, gelatin, collagen, atelocollagen, Hyaluronic acid, casein, agar, acacia, dextrin, ethyl cellulose, methyl cellulose, chitin, chitosan, mannan, carboxymethyl ethyl cellulose, carboxymethyl Cellulose sodium, polyethylene glycol, sodium alginate, polyvinyl alcohol, cellulose acetate, polyvinylpyrrolidone, polyfluorene oxide, polyethylene acetal diethylaminoacetate, albumin, And lactic acid/glycolic acid copolymer.

The polymer may be used singly or in combination of two or more kinds.

The sustained-release intraocular implant may also contain a pharmacologically active ingredient or a physiologically active ingredient other than a therapeutic agent for retinopathy. As such a component, the components as exemplified in the above examples can be used. The sustained-release intraocular implant is not limited to a solid, and may be in the form of a semi-solid, a gel, a fluid, or a liquid.

Sustained release contact lens preparation

Meanwhile, the ophthalmic preparation may, for example, be a sustained release contact lens preparation containing a therapeutic agent for retinopathy other than GGA and/or GGA in the contact lens itself. Such a sustained-release preparation may, for example, be a solution for immersing a contact lens in a therapeutic agent for retinopathy other than GGA and/or GGA, such as a cleaning solution, a preservation solution, a disinfectant, and a multipurpose maintenance solution (multipurpose). Solution), packaging preservation solution, etc. Alternatively, the contact lens manufacturing raw material, such as a constituent monomer of a contact lens polymer (hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, dimethyl group) The ethylene glycol acrylate, benzoin methyl ether, etc., a coloring agent, or an ultraviolet absorber is infiltrated with a therapeutic agent for retinopathy other than GGA and/or GGA, and is prepared by using these to produce a contact lens.

The sustained-release contact lens preparation may also contain a pharmacologically active ingredient or a physiologically active ingredient other than the therapeutic agent for retinopathy. As such a component, the components as exemplified in the above examples can be used.

The sustained release intraocular implant and the sustained release contact lens preparation may contain both a GGA and a GGA treatment agent for retinopathy, or may include only one of them. When only one of them is included, an ophthalmic preparation containing the other may be additionally used in the eye.

<Content of GGA>

The content of GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, more preferably 0.00005% by weight or more, more preferably 0.00008% by weight or more, and more preferably 0.0001% by weight or more, based on the total amount of the composition. More preferably, it is 0.0003% by weight or more, more preferably 0.0005% by weight or more, more preferably 0.0008% by weight or more, more preferably 0.001% by weight or more. At the same time, it may be 0.003% by weight or more, 0.005% by weight or more, 0.008% by weight or more, 0.01% by weight or more, 0.03% by weight or more, 0.05% by weight or more, 0.08% by weight or more, 0.1% by weight or more, and 0.3% by weight or more. 0.5% by weight or more, 0.8% by weight or more, and 1% by weight or more. In the above range, conjunctival hyperemia and corneal damage caused by the component (b) can be sufficiently suppressed, and the effect of preventing, improving, or treating retinopathy can be sufficiently obtained.

Further, the content of GGA in the ophthalmic preparation is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 30% by weight or less based on the total amount of the preparation. At the same time, it may be 10% by weight or less. In the above range, the effect of preventing, improving, or treating retinopathy can be fully obtained, and at the same time It becomes a formulation that is more clarified and less prone to fogging.

In addition, when the ophthalmic preparation is a solid preparation, for example, a liquid, a fluid, a gel, or a semi-solid preparation, the content of GGA in the preparation is preferably 10% by weight or less based on the total amount of the preparation. More preferably, it is 5% by weight or less, more preferably 3% by weight or less, still more preferably 2% by weight or less.

The content of GGA in the ophthalmic preparation may be, for example, about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 30% by weight, about 0.00001 to 10% by weight, and about 0.00003 to the total amount of the preparation. 90% by weight, about 0.00003 to 50% by weight, about 0.00003 to 30% by weight, about 0.00003 to 10% by weight, about 0.00005 to 90% by weight, about 0.00005 to 50% by weight, about 0.00005 to 30% by weight, about 0.00005 to 10% % by weight, about 0.00008 to 90% by weight, about 0.00008 to 50% by weight, about 0.00008 to 30% by weight, about 0.00008 to 10% by weight, about 0.0001 to 90% by weight, about 0.0001 to 50% by weight, about 0.0001 to 30% by weight %, about 0.0001 to 10% by weight, about 0.0003 to 90% by weight, about 0.0003 to 50% by weight, about 0.0003 to 30% by weight, about 0.0003 to 10% by weight, about 0.0005 to 90% by weight, about 0.0005 to 50% by weight , about 0.0005 to 30% by weight, about 0.0005 to 10% by weight, about 0.0008 to 90% by weight, about 0.0008 to 50% by weight, about 0.0008 to 30% by weight, about 0.0008 to 10% by weight, about 0.001 to 90% by weight, About 0.001 to 50% by weight, about 0.001 to 30% by weight, about 0.001 to 10% by weight, about 0.003 to 90% by weight, about 0.003 to 50% by weight, about 0.003 to 30% by weight, about 0.003 to 10% by weight, about 0.005 to 90% by weight, about 0.005 to 50% by weight, about 0.005 to 30% by weight, about 0.005 to 10% by weight, about 0.008 to 90% by weight, about 0.008 to 50% by weight, about 0.008 to 30% by weight, about 0.008 to 10% % by weight, about 0.01 to 90% by weight, about 0.01 to 50% by weight, about 0.01 to 30% by weight, about 0.01 to 10% by weight, about 0.03 to 90% by weight, about 0.03 to 50% by weight, about 0.03 to 30% by weight %, about 0.03 to 10% by weight, about 0.05 to 90% by weight, about 0.05 to 50% by weight, about 0.05 to 30% by weight, about 0.05 to 10% by weight, about 0.08 to 90% by weight, about 0.08 to 50% by weight , about 0.08 to 30% by weight, about 0.08 to 10% by weight, about 0.1 to 90% by weight, about 0.1 to 50% by weight, about 0.1 to 30% by weight, about 0.3 to 90% by weight, about 0.3 to 50% by weight, About 0.3 to 30% by weight, about 0.3 to 10% by weight, about 0.5 to 90% by weight, about 0.5 to 50% by weight, about 0.5 to 30% by weight, about 0.5 to 10% by weight, about 0.8 to 90% by weight, about 0.8 to 50% by weight, about 0.8 to 30% by weight, about 0.8 to 10% by weight, about 1 to 90% by weight, about 1 to 50% by weight, about 1 to 30% by weight, and about 1 to 10% by weight.

In addition, when the ophthalmic preparation is a solid preparation, for example, a liquid, a fluid, a gel, or a semi-solid preparation, the content of the GGA in the preparation may be, for example, about 0.00001 to the total amount of the preparation. 10% by weight, about 0.00001 to 5% by weight, about 0.00001 to 3% by weight, about 0.00001 to 2% by weight, about 0.00003 to 10% by weight, about 0.00003 to 5% by weight, about 0.00003 to 3% by weight, about 0.00003 to 2 % by weight, about 0.00005 to 10% by weight, about 0.00005 to 5% by weight, about 0.00005 to 3% by weight, about 0.00005 to 2% by weight, about 0.00008 to 10% by weight %, about 0.00008 to 5% by weight, about 0.00008 to 3% by weight, about 0.00008 to 2% by weight, about 0.0001 to 10% by weight, about 0.0001 to 5% by weight, about 0.0001 to 3% by weight, about 0.0001 to 2% by weight , about 0.0003 to 10% by weight, about 0.0003 to 5% by weight, about 0.0003 to 3% by weight, about 0.0003 to 2% by weight, about 0.0005 to 10% by weight, about 0.0005 to 5% by weight, about 0.0005 to 3% by weight, About 0.0005 to 2% by weight, about 0.0008 to 10% by weight, about 0.0008 to 5% by weight, about 0.0008 to 3% by weight, about 0.0008 to 2% by weight, about 0.001 to 10% by weight, about 0.001 to 5% by weight, about 0.001 to 3% by weight, about 0.001 to 2% by weight, about 0.003 to 10% by weight, about 0.003 to 5% by weight, about 0.003 to 3% by weight, about 0.003 to 2% by weight, about 0.005 to 10% by weight, about 0.005. Up to 5% by weight, about 0.005 to 3% by weight, about 0.005 to 2% by weight, about 0.008 to 10% by weight, about 0.008 to 5% by weight, about 0.008 to 3% by weight, about 0.008 to 2% by weight, about 0.01 to about 10% by weight, about 0.01 to 5% by weight, about 0.01 to 3% by weight, about 0.01 to 2% by weight, about 0.03 to 10% by weight, about 0.03 to 5% by weight, about 0.03 to 3% by weight, about 0.03 to 2 % by weight, about 0.05 to 10% by weight, about 0% .05 to 5% by weight, about 0.05 to 3% by weight, about 0.05 to 2% by weight, about 0.08 to 10% by weight, about 0.08 to 5% by weight, about 0.08 to 3% by weight, about 0.08 to 2% by weight, about 0.1 to 10% by weight, about 0.1 to 5% by weight, about 0.1 to 3% by weight, about 0.1 to 2% by weight, about 0.3 to 10% by weight, about 0.3 to 5% by weight, about 0.3 to 3% by weight, about 0.3% Up to 2% by weight, about 0.5 to 10% by weight, about 0.5 to 5% by weight, about 0.5 to 3% by weight, about 0.5 to 2% by weight, about 0.8 to 10% by weight, about 0.8 to 5% by weight, About 0.8 to 3% by weight, about 0.8 to 2% by weight, about 1 to 10% by weight, about 1 to 5% by weight, about 1 to 3% by weight, and about 1 to 2% by weight.

Meanwhile, in the case of the ophthalmic preparation solid preparation, the content of GGA in the preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and still more preferably 0.1 mg or more in the entire preparation. In the above range, the effect of preventing, ameliorating, or treating retinopathy can be sufficiently obtained, and side effects caused by the therapeutic agent for retinopathy other than GGA can be sufficiently suppressed. Meanwhile, the content of GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less in the entire preparation. In the above range, the effect of preventing, ameliorating, or treating retinopathy can be sufficiently obtained.

The content of GGA in the solid preparation may be, for example, about 0.001 to 1000 mg, about 0.001 to 100 mg, about 0.001 to 10 mg, about 0.01 to 1000 mg, about 0.01 to 100 mg, about 0.01 to 10 mg, or about 0.1 to the total amount of the preparation. 1000 mg, about 0.1 to 100 mg, about 0.1 to 10 mg.

<Contents of therapeutic agents for retinopathy other than GGA>

The content of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, more preferably 0.00005% by weight or more, and even more preferably 0.00008% by weight or more, based on the total amount of the preparation. More preferably, it is 0.0001% by weight or more, more preferably 0.0003% by weight or more, more preferably 0.0005% by weight or more. At the same time, it may be 0.0008 wt% or more, 0.001 wt% or more, 0.003 wt% or more, 0.005 wt% or more, 0.008 wt% or more, 0.01 wt% or more, 0.03 wt% or more, 0.05 wt% or more, and 0.08 wt% or more. 0.1% by weight or more. In the above range, various effects of suppressing adsorption of GGA in the container, suppressing turbidity of the preparation, and increasing the stability of GGA to heat and light can be sufficiently obtained, and the effect of preventing, improving, or treating retinopathy can be sufficiently obtained.

Further, the content of the therapeutic agent for retinopathy other than GGA is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 10% by weight or less based on the total amount of the preparation. It may be 5% by weight or less, or may be 1% by weight or less. In the above range, the side effects caused by the therapeutic agent for retinopathy other than GGA are sufficiently suppressed.

The content of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation may be, for example, about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 10% by weight, and about 0.00001 to 5, based on the total amount of the preparation. % by weight, about 0.00001 to 1% by weight, about 0.00003 to 90% by weight, about 0.00003 to 50% by weight, about 0.00003 to 10% by weight, about 0.00003 to 5% by weight, about 0.00003 to 1% by weight, about 0.00005 to 90% by weight %, about 0.00005 to 50% by weight, about 0.00005 to 10% by weight, about 0.00005 to 5% by weight, about 0.00005 to 1% by weight, about 0.00008 to 90% by weight, about 0.00008 to 50% by weight, about 0.00008 to 10% by weight , about 0.00008 to 5% by weight, about 0.00008 to 1% by weight, about 0.0001 to 90% by weight, about 0.0001 to 50% by weight, about 0.0001 to 10% by weight, about 0.0001 to 5% by weight, about 0.0001 to 1% by weight, About 0.0003 to 90% by weight, about 0.0003 to 50% by weight, about 0.0003 to 10% by weight, about 0.0003 to 5% by weight, about 0.0003 to 1% by weight, about 0.0005 to 90% by weight, about 0.0005 to 50% by weight, about 0.0005 to 10% by weight, about 0.0005 to 5% by weight, About 0.0005 to 1% by weight, about 0.0008 to 90% by weight, about 0.0008 to 50% by weight, about 0.0008 to 10% by weight, about 0.0008 to 5% by weight, about 0.0008 to 1% by weight, about 0.001 to 90% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, about 0.001 to 5% by weight, about 0.001 to 1% by weight, about 0.003 to 90% by weight, about 0.003 to 50% by weight, about 0.003 to 10% by weight, about 0.003. Up to 5% by weight, about 0.003 to 1% by weight, about 0.005 to 90% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.005 to 5% by weight, about 0.005 to 1% by weight, about 0.008 to 90% by weight, about 0.008 to 50% by weight, about 0.008 to 10% by weight, about 0.008 to 5% by weight, about 0.008 to 1% by weight, about 0.01 to 90% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight % by weight, about 0.01 to 5% by weight, about 0.01 to 1% by weight, about 0.03 to 90% by weight, about 0.03 to 50% by weight, about 0.03 to 10% by weight, about 0.03 to 5% by weight, and about 0.03 to 1 by weight. %, about 0.05 to 90% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.05 to 5% by weight, about 0.05 to 1% by weight, about 0.08 to 90% by weight, about 0.08 to 50% by weight , about 0.08 to 10% by weight, about 0.08 to 5 weight %, about 0.08 to 1% by weight, about 0.1 to 90% by weight, about 0.1 to 50% by weight, about 0.1 to 10% by weight, about 0.1 to 5% by weight, and about 0.1 to 1% by weight.

The content of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation is preferably 0.0001 part by weight or more, more preferably 0.0003 part by weight or more, more preferably 0.0005 part by weight or more, and more preferably 0.0008 part by weight or more, per part by weight of GGA. Preferably, more than 0.001 parts by weight, more preferably 0.003 More preferably, it is more preferably 0.005 parts by weight or more, more preferably 0.008 parts by weight or more, more preferably 0.01 parts by weight or more. At the same time, it may be 0.1 parts by weight or more. In the above range, various effects of suppressing GGA adsorption in a container, suppressing cloudiness of the composition, and increasing the stability of GGA to heat and light can be sufficiently obtained, and the effects of preventing, improving, or treating retinopathy can be sufficiently obtained.

Further, the content of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation is preferably 100,000 parts by weight or less, more preferably 8,000 parts by weight or less, more preferably 5,000 parts by weight or less, and 3,000 parts by weight or less based on 1 part by weight of GGA. More preferably, it is more preferably 1000 parts by weight or less, more preferably 800 parts by weight or less, more preferably 500 parts by weight or less, more preferably 300 parts by weight or less, more preferably 100 parts by weight or less. At the same time, it may be 10 parts by weight or less. In the above range, the side effects caused by the therapeutic agent for retinopathy other than GGA are sufficiently suppressed.

The content of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation may be, for example, about 0.0001 to 100,000 parts by weight, about 0.0001 to 8,000 parts by weight, about 0.0001 to 5,000 parts by weight, or about 1 part by weight of GGA. 0.0001 to 3000 parts by weight, about 0.0001 to 1000 parts by weight, about 0.0001 to 800 parts by weight, about 0.0001 to 500 parts by weight, about 0.0001 to 300 parts by weight, about 0.0001 to 100 parts by weight, about 0.0001 to 10 parts by weight, about 0.0003. To 100000 parts by weight, about 0.0003 to 8000 parts by weight, about 0.0003 to 5000 parts by weight, about 0.0003 to 3000 parts by weight, about 0.0003 to 1000 parts by weight, about 0.0003 to 800 parts by weight, about 0.0003 to 500 parts by weight, about 0.0003 to 300 parts by weight, about 0.0003 to 100 parts by weight, about 0.0003 to 10 parts by weight, about 0.0005 to 100,000 Parts by weight, from about 0.0005 to 8000 parts by weight, from about 0.0005 to 5000 parts by weight, from about 0.0005 to 3000 parts by weight, from about 0.0005 to 1000 parts by weight, from about 0.0005 to 800 parts by weight, from about 0.0005 to 500 parts by weight, from about 0.0005 to 300 parts by weight. Parts, about 0.0005 to 100 parts by weight, about 0.0005 to 10 parts by weight, about 0.0008 to 100000 parts by weight, about 0.0008 to 8000 parts by weight, about 0.0008 to 5000 parts by weight, about 0.0008 to 3,000 parts by weight, about 0.0008 to 1000 parts by weight. , about 0.0008 to 800 parts by weight, about 0.0008 to 500 parts by weight, about 0.0008 to 300 parts by weight, about 0.0008 to 100 parts by weight, about 0.0008 to 10 parts by weight, about 0.001 to 100,000 parts by weight, about 0.001 to 8,000 parts by weight, About 0.001 to 5000 parts by weight, about 0.001 to 3000 parts by weight, about 0.001 to 1000 parts by weight, about 0.001 to 800 parts by weight, about 0.001 to 500 parts by weight, about 0.001 to 300 parts by weight, about 0.001 to 100 parts by weight, about 0.001 to 10 parts by weight, about 0.003 to 100000 parts by weight, about 0.003 to 8000 parts by weight, about 0.003 to 5000 parts by weight, about 0.003 to 3000 parts by weight, about 0.003 to 1000 parts by weight, about 0.003 to 800 parts by weight, about 0.003 Up to 500 parts by weight, about 0.003 to 300 parts by weight, about 0.003 to 100 parts by weight, about 0.003 to 10 parts by weight, about 0.005 to 100,000 parts by weight, about 0.005 to 8,000 parts by weight, about 0.005 to 5,000 parts by weight, about 0.005 to 3,000 parts by weight, about 0.005 to 1000 parts by weight Parts by weight, from about 0.005 to 800 parts by weight, from about 0.005 to 500 parts by weight, from about 0.005 to 300 parts by weight, from about 0.005 to 100 parts by weight, from about 0.005 to 10 parts by weight, from about 0.008 to 100,000 parts by weight, from about 0.008 to 8,000 parts by weight. Parts, about 0.008 to 5000 parts by weight, about 0.008 to 3000 parts by weight, about 0.008 to 1000 parts by weight, about 0.008 to 800 Parts by weight, from about 0.008 to 500 parts by weight, from about 0.008 to 300 parts by weight, from about 0.008 to 100 parts by weight, from about 0.008 to 10 parts by weight, from about 0.01 to 100,000 parts by weight, from about 0.01 to 8,000 parts by weight, from about 0.01 to 5,000 parts by weight. Parts, about 0.01 to 3000 parts by weight, about 0.01 to 1000 parts by weight, about 0.01 to 800 parts by weight, about 0.01 to 500 parts by weight, about 0.01 to 300 parts by weight, about 0.01 to 100 parts by weight, about 0.01 to 10 parts by weight , about 0.1 to 100000 parts by weight, about 0.1 to 8000 parts by weight, about 0.1 to 5000 parts by weight, about 0.1 to 3000 parts by weight, about 0.1 to 1000 parts by weight, about 0.1 to 800 parts by weight, about 0.1 to 500 parts by weight, About 0.1 to 300 parts by weight, about 0.1 to 100 parts by weight, and about 0.1 to 10 parts by weight.

When the ophthalmic preparation is a solid preparation, the therapeutic amount of the therapeutic agent for retinopathy other than GGA in the ophthalmic preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and still more preferably 0.1 mg or more. In the above range, various effects of suppressing the adsorption of GGA in the container, increasing the stability of GGA to heat and light, and sufficiently obtaining the effect of preventing, improving, or treating retinopathy can be sufficiently obtained.

In addition, the content of the therapeutic agent for retinopathy other than GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less. In the above range, the side effects caused by the therapeutic agent for retinopathy other than GGA are sufficiently suppressed.

The content of the therapeutic agent for retinopathy other than GGA in the solid preparation may be, for example, 0.001 to 1000 mg, 0.001 to 100 mg, 0.001 to 10 mg, 0.01 to 1000 mg, 0.01 to 100 mg, 0.01 to 10 mg, 0.1 to the entire preparation. 1000mg, 0.1 to 100mg, 0.1 To 10mg.

pH

The pH at the time when the ophthalmic preparation is a moisture-containing composition is preferably 4 or more, more preferably 5.5 or more, more preferably 6 or more, and even more preferably 6.5 or more. In the above range, not only the GGA is excellent in heat and light stability, but also the effect of the present invention is more remarkable.

At the same time, it is better to be 9 or less, 8.5 or less is better, 8 or less is better, and 7.5 or less is better. In the above range, irritation to the eyes is suppressed.

Viscosity

The viscosity of the ophthalmic preparation of the present invention is appropriately set depending on the type and content of the formulation, the form of the preparation, the method of use, and the like, as long as it is physiologically or pharmaceutically acceptable. The viscosity at 20 ° C measured by a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1° 34' × R24) is preferably 0.01 to 10000 mPa ‧ s, preferably 0.05 to 8000 mPa ‧ s, 0.5 It is even better to 1000mPa‧s.

Concomitant/complex

The ophthalmic preparation of the present invention may be a single dosage form preparation (combination agent) containing a therapeutic agent for retinopathy other than GGA and GGA in one composition, or a preparation having two or more types of two or more types of components in combination. (Use the medicine together). In the latter case, for example, an ophthalmic composition containing GGA and a retina other than GGA having a combined use thereof may be mentioned. The ophthalmic composition for the disease treatment agent is used in combination (concomitant agent). Alternatively, an ophthalmic composition containing a therapeutic agent for retinopathy other than GGA and a combination of ophthalmic compositions containing GGA (combined drug) may be mentioned. In addition, it may be a composition having a therapeutic agent for retinopathy other than GGA and GGA, and a combination of a composition containing a specific additive and a specific pharmacological activity or physiologically active ingredient. When the preparation is used in combination, each composition may be filled in an individual container or a preparation preparation for use in a container which can be mixed at the time of use. When the preparation is used in combination, any of the two dosage forms or the three dosage forms may be used. From the viewpoints of suppressing the white turbidity effect, suppressing the effect of adsorption on a container, heat stabilization effect, and/or light stabilization effect, the composition of the present invention contains retinopathy other than GGA and GGA in one composition. The preparation of the therapeutic agent is preferred.

When the preparation of the present invention is a combined preparation of a composition containing GGA and a composition containing other components, the content of the GGA described above and the content of the therapeutic agent for retinopathy other than GGA, that is, the total composition The ratio of the total amount of the measurement.

container

The ophthalmic preparation of the present invention is usually contained or filled in a container (particularly, an ophthalmic container). The type of the container is not particularly limited, and examples thereof include a plastic container, a metal container, and a glass container. At the same time, it may also be exemplified that at least part or all of the contact surface with the preparation is selected from: plastic (for example, polyolefin, acrylic resin, terephthalate, 2,6-naphthalenedicarboxylate, polycarbonate). Ester, polymethyl decene, fluororesin, polyvinyl chloride Alkene, polyamine, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polyfluorene, polyimine, cellulose acetate, hydrocarbon substituted by halogen atom, etc.) A container made of at least one material selected from the group consisting of metal (aluminum or the like) and glass. Meanwhile, the container made of the above-mentioned materials means a ratio of 50% by weight or more, preferably 60% by weight or more, and more preferably 70% by weight or more, based on the weight of the container (body) per one serving. A container containing the above materials. Mixtures or copolymers of the above materials may also be used.

Examples of the polyolefin include polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (including isotactic Polypropylene, syndiotactic polypropylene, atactic polypropylene, etc., and ethylene/propylene copolymers.

Examples of the acrylic resin include acrylate such as methyl acrylate, methacrylate such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

Examples of the terephthalic acid esters include polyethylene terephthalate, trimethylene terephthalate, and polybutylene terephthalate.

Examples of the 2,6-naphthalenedicarboxylic acid ester include polyethylene naphthalate, butylene naphthalate, and the like.

Examples of the fluorine-containing resin may, for example, be a fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), a polyfluoroethylene, a polyvinyl fluoride, or a perfluoroalkoxy fluoro resin. ), a tetrafluoroethylene/hexafluoropropylene copolymer, an ethylene/tetrafluoroethylene copolymer, an ethylene/chlorotrifluoroethylene copolymer, and the like.

Examples of the polyamine can be exemplified by nylon or the like.

Examples of the polyacetal may be, in addition to those containing only an oxymethylene unit, a part of an oxygen-containing ethyl group.

Examples of the modified polyphenylene ether include, for example, polystyrene-modified polyphenylene ether.

Examples of the polyarylate may, for example, be an amorphous polyarylate or the like.

The polyimine may, for example, be an aromatic polyimine, and may be, for example, a polymer obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

Examples of the cellulose acetate may, for example, be cellulose diacetate or cellulose triacetate.

The hydrocarbon which may be substituted by a halogen atom may, for example, be a hydrocarbon such as methane, ethane, propane, butane, ethylene, propylene, 1-butene, 2-butene or 1,3-butadiene; Fluoromethane, trifluoromethane, tetrafluoromethane, 1,1-difluoroethane, 1,2-difluoroethane, 1-fluoropropane, 2-fluoropropane, 1,2-fluoropropane, 1,3- Fluoropropane, 1-fluorobutane, 2-fluorobutane, vinyl fluoride, vinylidene fluoride, 1,2-difluoroethylene, trifluoroethylene, tetrafluoroethylene, 3-fluoropropene, 1,3 - a fluorine-substituted hydrocarbon such as fluoropropene, 1,1,4,4-tetrafluorobutadiene or perfluorobutadiene; methyl chloride, dichloromethane, chloroform, tetrachloromethane, 1,1-dichloro Ethane, 1,2-dichloroethane, 1-chloropropane, 2-chloropropane, 1,2-chloropropane, 1,3-chloropropane, 1-chlorobutane, 2-chlorobutane, vinyl chloride 1,1-Dichloroethylene, 1,2-dichloroethylene, trichloroethylene, tetrachloroethylene, 3-chloropropene, 1,3-chloropropene, 1,1,4,4-tetrachlorobutadiene a hydrocarbon substituted with a chlorine atom such as perchlorobutadiene; methyl bromide, dibromomethane, bromoform, tetrabromomethane, 1,1-dibromoethane, 1,2-dibromoethane, 1-bromopropane, 2- Bromopropane, 1,2-bromopropane, 1, 3-bromopropane, 1-Bromobutane, 2-bromobutane, vinyl bromide, 1,1-dibromoethylene, 1,2-dibromoethylene, tribromoethylene, tetrabromoethylene, 3-bromopropene, 1,3-bromopropene a hydrocarbon substituted with a bromine atom such as 1,1,4,4-tetrabromobutadiene or perbromobutadiene; methyl iodide, diiodomethane, iodoform, tetraiodomethane, 1,1-diiodoethane 1,2-diiodoethane, 1-iodopropane, 2-iodopropane, 1,2-iodopropane, 1,3-iodopropane, 1-iodobutane, 2-iodobutane, iodoethylene, 1 , 1-diiodoethylene, 1,2-diiodoethylene, triiodethylene, tetraiodoethylene, 3-iodopropene, 1,3-iodopropene, 1,1,4,4-tetraiodobutadiene, all a hydrocarbon such as iodine butadiene substituted with an iodine atom.

The container material is selected from the group consisting of: terephthalate (especially, polyethylene terephthalate is preferred), polycarbonate, polymethyl decene, fluorine-substituted polyethylene (especially, Tetrafluoroethylene is preferred, 2,6-naphthalenedicarboxylate (especially, polyethylene naphthalate, polybutylene naphthalate is preferred), polyolefin (especially, polyethylene, polypropylene) At least one selected from the group consisting of polymethacrylates (especially, preferably methyl methacrylate) is preferred.

In the case of a container, a layer or film composed of the above materials may be formed on the inner surface of the container, or the container body may be formed from the above material. At the same time, it is preferable that at least a part of the surface in contact with the ophthalmic preparation is composed of the above materials, and it is preferable that the surface in contact with all of the surfaces is composed of the above materials.

At the same time, the container may be integrally formed or composed of two or more members. When the container is composed of two or more members, only one or all of the members may be composed of the above materials, and different materials may be used for the members. For example, in an eye drop container, an eye wash container, an eye ointment container, or the like, a container having a spout or a nozzle, All of the materials including the injection port or the nozzle may be formed of the above materials, or only the body portion other than the injection port or the nozzle may be formed of the above materials. At the same time, a layer or film composed of the above materials may be formed on the inner surface of all the portions, or a layer or film composed of the above materials may be formed only on the inner surface of the body portion.

The shape and capacity of the container, the thickness of the container wall, and the like are not particularly limited. The type of visible container, the shape, capacity, and wall thickness of the container are usually used.

For example, the capacity of the container may, for example, be about 0.01 to 1000 mL, more preferably about 0.1 to 500 mL, still more preferably about 1 to 100 mL, still more preferably about 1 to 20 mL. Meanwhile, the thickness of the container may, for example, be about 0.01 to 10 mm, more preferably about 0.05 to 5 mm, still more preferably about 0.1 to 3 mm.

Meanwhile, when the inner wall of the container forms a layer or a film formed by the above material, the formed layer or film may be laminated on the body, or may be formed by vapor deposition, plasma CVD, plasma polymerization, sputtering, or the like. membrane. The thickness of the layer or film formed of the above materials is not particularly limited and may be, for example, about 10 nm to 5 mm.

Subject lesion

The ophthalmic preparation of the present invention may be a lesion caused by degeneration, damage, or cell death of cells constituting the retina, or a retinopathy caused by a lesion of degeneration, damage, or cell death of cells constituting the retina.

Examples of such lesions, such as glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, sugar Urinary macular degeneration, hypertensive retinopathy, retinal vascular occlusion (retinal artery occlusion; central retinal vein occlusion, retinal vein occlusion such as central retinal venous occlusion), retinal arteriosclerosis, retinal tears, retinal rupture , macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented venous retinal choroidal atrophy, convoluted chorioretinal atrophy, no choroidal malformation, lens retinopathy, white spot retinitis, cone dystrophy, central halo Rotary choroidal atrophy, multi-UK cellular retinal dystrophy, yolk-like macular dystrophy, cystoid edema lesions of the macula, occult macular dystrophy, Sturgeon's disease, retinolysis, central serous chorioretinopathy Central retinopathy), spinal cerebellar atrophy type 7, familial exudative vitreoretinopathy, severe small cone cell syndrome, retinal vascular pattern, somatic megasexual optic atrophy, somatic chromosomal dominant choroidal drusen Familial Envelope film drusen, acute strip hidden outer retinal disease, tumor induced retinopathy, light damage, and ischemic retinopathy.

Among them, glaucoma, retinitis pigmentosa, senile macular degeneration, and diabetic retinopathy are suitable lesions, and glaucoma is a more suitable lesion.

Meanwhile, in the ophthalmic preparation of the present invention, the subject may be a lesion caused by damage to any cells constituting the retina or damage to any cells constituting the retina. The cells constituting the retina may be, for example, retinal ganglion cells, axon-free neurons, horizontal cells, Muller glial cells, bipolar nerve cells, retinal cells. (cone cells, rod cells), and retinal pigment epithelial cells. It is particularly suitable for identifying lesions that have damage to retinal ganglion cells, or retinal pigment epithelial cells, or lesions caused by damage to such cells.

Meanwhile, the preparation of the present invention may also be a layer constituting the retina, that is, an inner limiting membrane, a nerve fiber layer, a ganglion cell layer, an inner plex layer, an inner granular layer, an outer plexus layer, an outer granular layer, an outer membrane, Any of the retinal neuroepithelial layer and the retinal pigment epithelial layer that is damaged, or a lesion caused by damage to any of these layers. In particular, a lesion damaged by a ganglion cell layer, an inner granular layer, or an outer granular layer is a more suitable subject.

The target lesion may be one type or two or more types.

Therefore, the ophthalmic preparation of the present invention can be used as a preparation for preventing, ameliorating, or treating retinopathy, inhibiting degeneration, damage, or cell death of retinal cells, or protecting retinal cells. Meanwhile, as shown in the example items, since GGA has an effect of inducing axonal elongation of cells such as the retina, it can be used for promotion or induction of (retinal) axon elongation, promotion of (retina) cell function, or A preparation for the improvement or improvement of the living state of retinal cells.

In the present invention, "prevention" includes avoidance, delay, or reduction in the incidence of the disease, and "improvement" and "treatment" include reduction of symptoms, suppression of symptoms, and healing or recovery.

Instructions

When the preparation of the present invention is an eye drop, the eye drop containing the above-mentioned concentration of GGA can be spotted in the following manner, for example, about 1 to 5 drops per one time. More preferably from about 1 to 3 drops, more preferably from about 1 to 2 drops, from about 1 to 7 times on the 1st, more preferably from about 1 to 5 times, still more preferably from about 1 to 3 times.

Meanwhile, when the preparation of the present invention is an eye-washing agent, the eye-washing agent containing the above-mentioned GGA can be washed in the following manner, for example, about 1 to 20 mL per one time, about 1 to 10 times a day, about 1 to 5 times better.

Meanwhile, when the preparation of the present invention is an ophthalmic ointment, an ophthalmic ointment containing GGA of the above concentration may be applied to the eye in the following manner, for example, about 0.001 to 5 g per one time, about 1 to 7 times a day, to 1 to 5 times on the 1st is better, and 1 to 3 times on the 1st is better.

Meanwhile, when the preparation of the present invention is an intraocular injection, an injection containing GGA of the above concentration may be injected in the following manner, about 0.005 to 1 mL per one time, about 1 to 3 times from 1 to 14 days, to 1 The second time is better.

At the same time, the preparation of the present invention is used for the contact lens solution (cleaning solution, preservation solution, disinfectant solution, multi-function maintenance solution, packaging preservation solution), cornea for transplantation, etc., when the eye tissue preservation agent or the infusion solution during surgery is used. The composition containing the above-mentioned concentration of GGA can be used in the usual usage amount of such a preparation.

Meanwhile, when the preparation of the present invention is a sustained release contact lens preparation, the contact lens containing the above amount of GGA can be replaced with a new one in the following manner, for example, about 1 to 3 times from 1 to 14 days, preferably 1 time. .

Meanwhile, in the case where the preparation of the present invention is a sustained-release intraocular implant, there is a case where it is not replaced with a new implant, and there is also a case where a new implant containing the above-mentioned amount of GGA is replaced, in the case of replacement In time, it can be replaced once, for example, from about 1 day to 10 years. For example, if the implant of the posterior eye is longer, the replacement period is longer, and the new implant is replaced once between about 1 and 14 days.

However, the dosage of GGA on the 1st day when the ophthalmic preparation of the present invention is used is preferably 50 ng or more, more preferably 500 ng or more, and even more preferably 5 μg or more. Further, the amount of GGA administered on the 1st is preferably 50 mg or less, more preferably 20 mg or less, and still more preferably 10 mg or less.

The dose of the GGA on the 1st can be, for example, about 50 ng to 50 mg, about 50 ng to 20 mg, about 50 ng to 10 mg, about 500 ng to 50 mg, about 500 ng to 20 mg, about 500 ng to 10 mg, about 5 μg to 50 mg, or about 5 μg to 20 mg, about 5 μg to 10 mg.

In addition, the dosage of the component (b) (the therapeutic agent for retinopathy other than GGA) in the ophthalmic preparation of the present invention is preferably 50 ng or more, more preferably 500 ng or more, and more preferably 5 μg or more. Better yet. Further, the amount of the component (b) to be administered on the 1st day is preferably 50 mg or less, more preferably 20 mg or less, and still more preferably 10 mg or less.

The dose of the component (b) for one day can be, for example, 50 ng to 50 mg, 500 ng to 50 mg, 5 μg to 50 mg, 50 ng to 20 mg, 500 ng to 20 mg, 5 μg to 20 mg, 50 ng to 10 mg, 500 ng to 10 mg, 5 μg. To 10mg.

When the ophthalmic preparation of the present invention is administered to the eye, the method of administration varies depending on the type of the preparation, and may be exemplified by eye drops, eye wash, application to the eyes, spray on the eyes, implantation into the eyes, and assembly invisibility. Glasses, injection in the vitreous and other eyes.

When the ophthalmic preparation of the present invention is a combined preparation comprising a composition containing GGA and a composition containing the component (b), the composition containing the GGA and the composition containing the component (b) may be simultaneously administered. Included within, for example, within 12 hours, within 6 hours, or within 2 hours, Any of the composition of GGA and the composition containing the component (b) is left behind. When there is a gap between the two, it can be administered first, but after the composition containing the GGA is administered, the composition containing the component (b) can be administered more effectively to inhibit corneal damage and conjunctival hyperemia. .

other

The present invention comprises: (a) GGA, and (b) a retinopathy therapeutic agent (other than GGA) coexisting in an ophthalmic composition, thereby imparting inhibition to the ophthalmic composition (b) retinopathy A method of treating conjunctival hyperemia and/or corneal damage caused by a therapeutic agent (other than GGA). In other words, the method reduces the (b) retinopathy therapeutic agent by coexisting (a) GGA, and (b) a retinopathy therapeutic agent (other than GGA) in the ophthalmic composition (however, A method of side effects of conjunctival hyperemia and/or corneal damage which is other than GGA.

When the (a) GGA and (b) retinopathy therapeutic agents (other than GGA) coexist, the side effects of (b) retinopathy therapeutic agents (other than GGA) are suppressed or reduced. It is preferable to coexist for one day or more, three days or more, or one week or more. Further, the coexistence is carried out at about 1 to 80 ° C, and it is preferably carried out at a temperature of about 1 to 70 ° C, particularly at a temperature of 1 to 30 ° C. At the same time, coexistence can be performed under shading, or under non-shading, but it is better to perform under shading.

Meanwhile, the present invention comprises a method of inhibiting white turbidity of an ophthalmic composition by coexisting (a) GGA and (b) a therapeutic agent for retinopathy (other than GGA) in an ophthalmic composition.

The white turbidity of the ophthalmic composition containing GGA is particularly likely to occur when the concentration of GGA in the ophthalmic composition is high. According to the method of the present invention, the concentration of the GGA is 0.01% by weight or more, particularly preferably 0.03% by weight or more, particularly preferably 0.05% by weight or more, particularly preferably 0.08% by weight or more, and particularly preferably 0.1% by weight or more. Inhibit white turbidity. Further, in general, the concentration of GGA is 10% by weight or less to suppress white turbidity.

At the same time, coexistence, that is, in the GGA-containing ophthalmic composition, (b) the preparation of a retinopathy therapeutic agent (other than GGA), or the (b) retinopathy therapeutic agent (except GGA) The GGA in the ophthalmic composition is applied at about 1 to 80 ° C, and it can be carried out at a temperature of about 1 to 70 ° C. Further, the method of the present invention suppresses white turbidity of the ophthalmic composition at a low temperature. The "low temperature" may be, for example, 10 ° C or lower, particularly preferably 6 ° C or lower, and particularly preferably 4 ° C or lower. Meanwhile, the lower limit of the "low temperature" may be a temperature at which the composition does not freeze, for example, -10 ° C or higher, particularly preferably -5 ° C or higher, more preferably 0 ° C or higher.

At the same time, the coexistence can be performed under shading, or can be performed under non-shading, and is preferably performed under shading.

The present invention comprises: (a) GGA and (b) a retinopathy therapeutic agent (other than GGA) coexisting in an ophthalmic composition, thereby inhibiting GGA adsorption in a container (particularly, an ophthalmic container) ) on the method. This method, in other words, inhibits the properties of GGA adsorbed in the ophthalmic container by coexisting (a) GGA and (b) a therapeutic agent for retinopathy (other than GGA) in the ophthalmic composition. method.

The type of the container (particularly, the container for ophthalmology) is as described in the ophthalmic preparation of the present invention.

When coexistence of (a) GGA and (b) retinopathy therapeutic agent (other than GGA), that is, inhibition of GGA adsorption to the container, it is preferred to coexist for one day or more, three or more days, or one week or more. Just fine. Moreover, the coexistence is carried out at about 1 to 80 ° C, wherein it is preferably carried out at a temperature of from about 1 to 70 ° C, especially at a temperature of from about 1 to 30 ° C. At the same time, the coexistence can be performed under shading, or can be performed under non-shading, and is preferably performed in shading.

The present invention comprises: (a) GGA, and (b) a retinopathy therapeutic agent (other than GGA) coexisting in an ophthalmic composition to improve heat and/or light stability of GGA. method.

When coexistence of (a) GGA and (b) therapeutic agents for retinopathy (except for GGA), that is, to improve the stability of heat and/or light of GGA, it is preferable to coexist for one day or more and three days. Above, or more than one week.

In the present invention, the improvement in the stability of heat is determined by increasing the GGA residual ratio when the ophthalmic composition is allowed to stand at 40 ° C for 7 days, and is specifically determined by the method described in the examples. At the same time, the improvement of the stability of light is determined by increasing the GGA residual rate when the ophthalmic composition is irradiated with light of 1.3 million l x ‧ h, specifically by the method described in the examples .

Meanwhile, the coexistence is carried out at about 1 to 80 ° C, wherein it is preferably carried out at a temperature of about 1 to 70 ° C, particularly at a temperature of about 1 to 30 ° C. Simultaneously, Coexistence can be performed under shading, or under non-shading, and preferably under shading. The ophthalmic composition to be prepared is usually stored at a temperature of about 1 to 30 ° C, and may be placed at a temperature of about 1 ° C or more and about 70 ° C or less or about 80 ° C or less in the preparation of the ophthalmic composition. .

In each method of the present invention, the ophthalmic composition in preparation corresponds to an ophthalmic composition. In other words, in the respective methods of the present invention, when the (a) GGA and (b) components are present together in the composition for forming the ophthalmic composition, it corresponds to "coexistence".

In the method of the present invention, the ophthalmic composition containing the (a) GGA and (b) component or the ophthalmic composition prepared in the preparation, whether it is contained in a container (particularly an ophthalmic container) or not, as long as the ophthalmology The ophthalmic composition in the composition or preparation contains (a) GGA and (b) components, which corresponds to "(a) GGA and (b) components coexist."

(Example)

Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited thereto. Further, in the following examples, the content of the component may be expressed by w/v%, and the component content expressed by w/v% and the component content expressed by weight% in consideration of the composition of each of the samples. Essentially the same value.

Further, the container used in the following tests was about 0.5 to 1.5 mm in thickness.

(1) Modulation of geranylgeranyl ketone acetone

Commercially available teprenone (all-trans isomer: 5Z single-cis isomer The product = weight ratio of 3:2) (Wako Pure Chemical Industries Co., Ltd.), and the all-trans isomer was purified by silica gel chromatography.

Specifically, silicone (PSQ60B Fuji Silysia Chemical Co., Ltd.) was filled in a glass tube, and separated and purified by a mobile phase (n-hexane: ethyl acetate = 9:1). After separation, each fraction was concentrated and dried under reduced pressure, and the system of all-trans isomers was determined by GC and ¹ H-NMR (solvent: deuterated chloroform, internal standard: tetramethyl decane). And structure (productivity is about 20%).

At the same time, the 5Z monocis isomer was purified from commercially available teprenone in the same manner as above.

<GC measurement conditions>

Column: DB-1 (J & W scientific, 0.53mm × 30m, film thickness 1.5μm)

Column temperature: 200 ° C → 5 ° C / min → 300 ° C (10 minutes)

Gasification tank temperature: 280 ° C

Detector temperature: 280 ° C

Carrier gas: helium

Hydrogen pressure: 60kPa

Air pressure: 50kPa

Supplemental gas pressure: 75kPa (nitrogen gas)

Full flow: 41mL/min

Column flow: 6.52mL/min

Linear speed: 58.3cm/sec

Split ratio: 5:1

Injection volume: Inject 1 μL of 0.1 g/100 mL (ethanol solution) sample

The commercially available teprenone and the all-trans isomer purified as described above are mixed in any ratio to prepare an all-trans isomer: 5Z monocis isomer (weight ratio) = 8: 2 GGA. At the same time, it was mixed with the 5Z monocis isomer purified as described above to prepare an all-trans isomer: 5Z monocis isomer (weight ratio) = 2:8 GGA. Since the stability of the mixing cannot be ensured, it is modulated at the time of use.

(2) Assessment of the protective effect of retinal nerve cells that avoid hypoxic/low glucose-induced ischemic cell death

The progression of visual field damage in glaucoma is associated with the death of optic ganglion cells (RGC) caused by insufficient blood flow near the optic nerve (Folia Pharmacol. Jpn. 128, 255-258 (2006)). Using PC12, PC12 is a representative neural cell strain constructed from rat adrenal medullary pheochromocytoma tumors and is used as a model cell for RGC function assessment (J Neurosci Res. 2000 May 15; 60(4):495- 503.), the cytoprotective effect of GGA to avoid hypoxic/low glucose-induced ischemic cell death was tested.

(measuring method)

The test substance was prepared as follows. That is, the test materials were four GGAs containing a full trans isomer and a 5Z monocis isomer at a weight ratio of 10:0, 8:2, 6:4, and 0:10. Weigh 100mg of each GGA, 0.25mg The antioxidant DL-α-tocopheryl acetate (Wako Pure Chemical Industries, Ltd.) was dissolved in 789 mg of 100% ethanol, and the same procedure was used except that GGA was not used as a base. 10:0, 8:2, and 6:4 GGA dissolved in 789 mg of 100% ethanol, supplemented with 10% (v/v) horse serum (DS Pharma Biomedical), 5% (v/v) High-glucose concentration (4.5 g/L) of fetal bovine serum (first chemical company) in Dulbecco modified Eagle basal medium (DMEM), diluted in a concentration such that the all-trans isomer was substantially 30 μM-adjusted, and The 0:10 GGA containing only the 5Z monocis isomer was diluted to 30 μM. The base was also diluted at the same dilution ratio as the GGA of the 6:4 weight ratio of the all-trans isomer to the 5Z monocis isomer.

In a 96-well microplate (IWAKI) coated with collagen IV, PC12 (obtained by DS Pharma Biomedical Co., Ltd.) was seeded with 100 μL of each of 2.0 × 10 ⁴ cells per well in the above DMEM. Incubation was carried out for 48 hours at 37 ° C under 5% CO ₂ .

After 48 hours of culture, the cell culture supernatant was removed, and exchanged with a pre-prepared GGA-containing DMEM, followed by incubation at 37 ° C, 5% CO ₂ for 2 hours. After 2 hours of culture, it was exchanged with DMEM supplemented with 2% horse serum and 1% fetal bovine serum at a low glucose concentration (1.0 g/L), and used at 37 ° C, 5% CO ₂ , and low oxygen concentration. Anaero Pack 5% (Mitsubishi Gas Chemical Company) was changed to 0% O ₂ and cultured for 8 hours. At the same time, DMEM supplemented with 2% (v/v) horse serum, 1% (v/v) fetal calf serum, high glucose concentration (4.5 g/L), and 37 ° C, 5% CO ₂ , usually The culture was carried out for 8 hours at an oxygen concentration as an untreated group.

(test results)

After culturing for 8 hours, 100 μL of each well was mixed with Cell Titer-Glo (Promega) and PBS in an equal amount, and the ATP reaction with living cells was measured with a Luminometer (GloMax; manufactured by Promega). The amount of luminescence generated. The effect of oxidative stress from hydrogen peroxide on the protection of cells via GGA is based on the measured amount of luminescence, and the cell survival rate is calculated and evaluated according to the following formula.

Cell survival rate (%) = [(luminescence amount of base or GGA treatment group) / (luminescence amount of untreated group)] × 100

The result is shown in Fig. 1. The results showed that the cell viability of all GGA treatment groups was significantly higher than that of the base treatment group (n=10, *P<0.05, **P<0.01, according to Tukey-Kramer assay).

(3) Evaluation of the induction effect of axonal elongation using a rat-derived retinal ganglion cell (RGC) cultured cell line

The progression of visual field damage in glaucoma is associated with the death of optic ganglion cells (RGC) caused by insufficient blood flow near the optic nerve (Folia Pharmacol. Jpn. 128, 255-258 (2006)). Therefore, the axonal elongation of GGA was tested in a rat-derived retinal nerve culture cell line (Current protocols in Neuroscience 3.22.1-3.22.10, October 2010), which is widely used as a research tool for retinopathy such as glaucoma. The induction effect.

(measuring method)

Four-day-old Wistar rats (Japan SLC Co., Ltd.) were euthanized and eyeballs were removed by cervical dislocation. The extracted eyeball was immersed in 70% ethanol for 10 seconds, and then transferred to a Hank balanced salt solution containing 100 U/mL penicillin and 100 μg/mL chain microtin, and removed under a stereo microscope using surgical scissors and forceps. The cornea, iris, lens and vitreous body are harvested and retinal tissue is extracted. The extracted retinal tissue was transferred to 5 mL of L-cysteamine containing 100 U/mL penicillin, 100 μg/mL chain microtin, nerve cell culture supplement (B27 ^TM -Supplement, manufactured by Invitrogen), and 1 μM. The acid (Xiehe Fermentation Technology Co., Ltd.) and a 15 U/mL papain (Sigma-Aldrich) nerve cell culture medium (Neurobasal, manufactured by Invitrogen) were centrifuged at 37 ° C for 30 minutes. After 30 minutes, the supernatant was removed, containing 100U / mL penicillin, 100μg / mL chain micro pixel, B27 ^TM -Supplement of Neurobasal washed twice. After washing, 2 mL of Neurobasal was added, and the tissue was transferred to a small cell block by pipetting with a dry heat sterilization Piper pipette (Hilgenberg), and then transferred to a previously prepared 50 mL of Neurobasal. After centrifugation at 900 × g for 5 minutes and removal of the supernatant, it was again suspended in 6 mL of Neurobasal to prepare a cell suspension. The cell suspension was passed through a 40 μm mesh nylon cell filter (BD, Japan) to remove the agglutinated cell mass, and then the cells were seeded in a 6-well microplate coated with poly-D-lysine/laminin. The plate (Japan BD Co., Ltd.) was cultured at 37 ° C under 5% CO ₂ .

The test substance was a 5Z monocis isomer and two GGAs in a weight ratio of 2:8 containing a mixture of the all-trans isomer and the 5Z monocis isomer. 100 mg of each GGA, 0.25 mg of an antioxidant substance of DL-α-tocopheryl acetate (Wako Pure Chemical Industries, Ltd.) was weighed and dissolved in 789 mg of 100% ethanol, and was prepared in the same manner except that GGA was not contained. As a base. The 5Z monocis isomer dissolved in 789 mg of 100% ethanol: GGA (5Z monocis isomer) with a weight ratio of all trans isomer of 0:10, 2:8 GGA mixture, adjusted Is a 5Z single cis isomer substantially containing 3 μM, and the base is added to the cell culture supernatant 2 hours after seeding the cells in the same dilution ratio as in the preparation of 6:4 GGA. The cells were cultured at 37 ° C under 5% CO ₂ for 48 hours.

(result)

After 48 hours of culture, the cell culture supernatant was removed, and the cells were fixed at room temperature for 30 minutes at room temperature with 4% polyoxymethylene/phosphate buffer (Wako Pure Chemical Industries, Ltd.) and 100% methanol (Wako Pure Chemical Industries, Ltd.). . After washing the cells with phosphate buffer (PBS, Kohjin Bio), 2% (w/v) bovine serum albumin (Sigma-Aldrich), 0.05% (v/v) Tween 20 (Sigma-Aldrich) In PBS, blocked for 30 minutes at room temperature. After 30 minutes, a 1000-fold dilution of β-III tubulin (Promega) was prepared in PBS, and 1 mL of each was added to each well, followed by incubation at room temperature for 2 hours. After 2 hours, the antibody dilution was removed and washed 3 times with PBS. A 1000-fold dilution of Alexa Fluor 488 Goat Anti-mouse antibody (Invitrogen) was prepared in PBS, and 1 mL of each was added to each well, followed by incubation at room temperature for 1 hour. After one hour, the antibody dilution was removed, and after washing three times with PBS, 3 mL of each PBS was added to each well, and each well was observed by an image cell meter (In Cell Analyzer 1000, manufactured by GE Health Care Bioscience). The average value of the axon length (μm) of the fluorescently stained RGC was calculated at any four points (excitation light wavelength 475 nm, fluorescence wavelength 535 nm).

The result is shown in Fig. 2. The results showed that the axon induction of each GGA treatment group in which the weight ratio of the all-trans isomer to the 5Z monocis isomer was 0:10, and 2:8 was stronger than that of the base treatment group.

(4) Assessment of inhibition of hyperemia Combination of latanoprost and GGA

Six rabbits (Japanese white species) were spotted with only 30 μL of GGA-containing eye drops (composed as shown in Table 1) in one eye. In the GGA aspect, the weight ratio of the all-trans isomer to the 5Z monocis isomer is 10:0. Meanwhile, an eyedrop containing 0.005 w/v% of latanoprost (product name: Xalatan Eye Drops 0.005%, Pfizer Co., Ltd.) was spotted at 30 μL each in both eyes. After 4 hours of eye-opening, the conjunctiva of the upper eyelid of the rabbit was inverted, and the degree of congestion observed in 30 seconds was quantified according to the criteria of Table 2. Since the eye and congestion assessments are performed by different testers, they are tested under blind conditions.

The result is shown in Fig. 3. As a result, conjunctival hyperemia was significantly inhibited by the side effects of latanoprost by using GGA in combination with latanoprost in a prostaglandin-based agent.

Combination of fasudil hydrochloride and GGA

Six rabbits (Japanese white species) were spotted with only 30 μL of GGA-containing eye drops in one eye. In the GGA aspect, the weight ratio of the all-trans isomer to the 5Z monocis isomer is 10:0. After lapse of 2 hours, fasudil hydrochloride (Wako Pure Chemical Industries, Ltd.) was dissolved in PBS to obtain a 0.02 w/v% solution, and each of the rabbit eyes was spotted at 30 μL. After 4 hours of eye-dropping, the conjunctiva of the upper eyelid of the rabbit was inverted, and the degree of congestion observed in 30 seconds was quantified according to the criteria of Table 1 above. Since the eye and congestion assessments are performed by different testers, they are tested under blind conditions.

The result is shown in Fig. 4. As a result, conjunctival hyperemia of the side effect of fasudil hydrochloride was remarkably suppressed by using GGA in fasudil hydrochloride of a ROCK inhibitor.

(5) Assessment of inhibition of cytotoxicity experiment method

In the GGA aspect, a GGA having a weight ratio of the all-trans isomer to the 5Z monocis isomer of 10:0 is used. 100 mg of GGA and 0.25 mg of an antioxidant-containing α-tocopherol (Wako Pure Chemical Industries, Ltd.) were weighed and dissolved in 789 mg of 100% ethanol. The GGA dissolved in ethanol was used to modify the Eagle basal medium using Dulbecco at a final concentration of 300 μM. /Ham F-12 was mixed in a liquid medium (DMEM/F-12, manufactured by Invitrogen) in an equal ratio and dissolved in the liquid medium. A person prepared in the same manner except for the absence of GGA was used as a base.

Human corneal epithelial cells (HCET) were seeded in a 96-well microplate (Corning) at a rate of 3.0 × 10 ⁴ cells per well, supplemented with 0.5% DMSO (Wako Pure Chemical Industries, Ltd.), 10 ng/ mL epithelial cell growth trophic factor (R & D), 5 μg/mL insulin (Invitrogen), and 5% (v/v) fetal bovine serum (first chemical company) Dulbecco modified Eagle basal medium/Ham F- The medium was mixed in a liquid medium (DMEM/F-12, manufactured by Invitrogen) in an equal ratio of 12, and cultured at 37 ° C under 5% CO ₂ .

After culturing for 24 hours, the eye drops were diluted with the final concentration in the culture supernatant to be 1%, and an eye drop containing thiazolamine maleate 0.5 w/v% was added (product name: 滴目露( Timoptol) 0.5% eye drops (Shentian Pharmaceutical Co., Ltd.), or eye drops containing 1w/v% of Kangshumu hydrochloride (product name: Trusopt eye drops 1%, MSD). At the same time, the GGA solution or the base was added so that the final concentration in the culture supernatant was 3 to 30 μM, and the mixture was further cultured.

After 48 hours of culture, the cell culture supernatant was removed, 200 μL of each PBS was added, and then PBS was removed. The cell viability assay Cell Titer-Glo (Promega) was mixed with PBS in an equal amount, and 100 μL of each well was added, and the amount of luminescence generated by the reaction with ATP in the living cells was measured with a Luminometer (GloMax; manufactured by Promega). The cytotoxicity caused by glaucoma eye drops is based on the protective effect of GGA. The amount of light, the cell survival rate calculated according to the following formula.

Cell survival rate (%) = [(luminescence amount of base or GGA treatment group) / (luminescence amount of untreated group)] × 100

result

The result is shown in Fig. 5. The β-blocking agent, timolol maleate or the carbonic anhydrase inhibitor, Kangshumu hydrochloride, reduces the cell survival rate of human corneal epithelial cells and is therefore cytotoxic. The cytotoxicity of timolol and chlorhexidine hydrochloride was significantly inhibited by the use of GGA in the combination of timolol maleate or konazol hydrochloride. Since the corneal epithelial damage is known to be associated with eye irritation, it is speculated that GGA also inhibits eye irritation when the beta blocking agent and the carbonic anhydrase inhibitor are spotted.

(6) Inhibition of the composition of white turbidity

In the surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C, add teprenone (Wako Pure Chemical Industries Co., Ltd.), teprenone and latanoprost, or teprenone And thiacycline maleate, dissolved in a hot water bath at 65 ° C for 2 minutes to dissolve, then added water at 65 ° C, mixed and stirred into a homogeneous solution. This solution was filtered using a filter membrane having a pore size of 0.2 μm (Bottle Top Filter manufactured by Thermo Fisher Scientific Co., Ltd.) to prepare a clear eyedrop containing the composition shown in Table 3.

The eye drops were dispensed into a 96-well microplate (flat bottom, polystyrene) by using a measuring pipette. In the production, the absorbance at 660 nm (temperature in the apparatus of 20 to 25 ° C) was measured using a microdisk analyzer (Versa Max, manufactured by Molecular Devices Co., Ltd.). The absorbance at 660 nm of each sample was taken as an indicator of white turbidity (turbidity) with reference to JIS K0101 (Industrial Water Test Method, Transmittance Measurement).

As a result, by using GGA in combination with a prostaglandin-based agent or a β-blocking agent, the turbidity of the GGA-containing composition is lowered, and white turbidity is suppressed.

(7) Inhibition of GGA adsorption in containers

The following procedures were used to prepare tepreperone (Wako Pure Chemical Industries Co., Ltd.), teprenone and latanoprost, teprenone and timolol, and teprenone and hydrochloric acid. Shu Dier eye drops. The composition of each eyedrop is shown in Table 4 and Table 5.

Specifically, in the surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C, teprenone, teprenone and latanoprost, teprenone and timolol were added. Maleate, or teprenone and fasudil hydrochloride, dissolved in a hot water bath at 65 ° C for 2 minutes to dissolve, then add water at 65 ° C, mix and stir each buffer to become homogeneous The solution is adjusted to pH and osmotic pressure with hydrochloric acid or sodium hydroxide. This solution was filtered through a filter membrane (Bottle Top Filter manufactured by Thermo Fisher Scientific Co., Ltd.) having a pore size of 0.2 μm to prepare a clarified sterile eye drop.

In addition, in each of the operations, it is determined by HPLC, which will be described later, that the content of the GGA is not adsorbed on the device or the like, and the content is lowered.

Each eyedrop was dispensed into a 15 mL-capacity plastic container with 5 mL of a whole pipette, and sealed. The material and capacity of the container are described in Table 6 which will be described later. These were placed in an upright standing state in the test tube rack, and a stability test was carried out at 40 ° C and 75% RH for 8 hours. Teprenone (g/100 mL) in each ophthalmic solution at the time of post-production and after standing for 8 hours was quantified by the aforementioned HPLC conditions, and the GGA residual ratio (%) was calculated.

The concentration of GGA in the preparation was determined as follows.

Method for determining GGA concentration

In the case of the Japanese Pharmacopoeia, "Prepone standard (all-trans isomer: 5Z single cis isomer = weight ratio of about 6:4, manufactured by the General Consortium Pharmaceutical Medical Device Regulatory Science Consortium)", or Teprenone (Wako Pure Chemical Co., Ltd.) as a standard product, according to the Japanese medicinal food review issued No. 0412007 "Tipuri The measurement conditions of the dissolution test contained in the ketone 100 mg/g fine granules are the area values (Ac) of the 5Z monocis isomer and the area value of the all-trans isomer under the following HPLC measurement conditions. (At), the concentration of GGA contained in each eyedrop was measured. Furthermore, teprenone (all-trans isomer: 5Z single cis isomer = weight ratio 3:2) is the total amount of all-trans isomers and 5Z mono-cis isomers as GGA. Calculated based on the content.

<HPLC measurement conditions>

Detector: UV spectrophotometer (measuring wavelength: 210 nm)

Column: YMC-Pack ODS-A (inner diameter 4.6mm, length 15cm, particle size 3μm)

Column temperature: 30 ° C

Mobile phase: 90% acetonitrile solution

Flow rate: 1.2 to 1.3 mL/min (dissolved in the order of 5Z mono-cis isomer, all-trans isomer)

Injection volume: 5 μL of 0.05g/100mL sample

The GGA-containing ophthalmic composition is prepared by formulating a prostaglandin-based latanoprost, a sympathetic β-blocking agent, timolol, or a ROCK inhibitor, fasudil hydrochloride. Significantly increase the residual rate of GGA.

Between the polystyrene container with the ophthalmic agent and the polypropylene container There is a difference in the GGA content, and it can be seen that the adsorption of GGA on the container wall is inhibited by the formulation of latanoprost, timolol, or fasudil hydrochloride.

The containers used in this experiment are described in Table 6.

(8) Assessment of thermal stability of GGA

The eye drops containing teprenone, latanoprost, timolol and fasudil hydrochloride, respectively, were prepared as follows. The composition of each eyedrop is shown in Table 7.

Specifically, in the surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C, teprenone, or latanoprost, timolol, or hydrochloric acid is added. Fasudil, dissolved in a hot water bath at 65 ° C for 2 minutes to dissolve, then add water at 65 ° C, then mix the buffer and stir into a homogeneous solution, adjust the pH and permeate with hydrochloric acid or sodium hydroxide Pressure. This solution was filtered using a filter membrane having a pore size of 0.2 μm (Bottle Top Filter manufactured by Thermo Fisher Scientific Co., Ltd.) to prepare a clarified sterile eye drop. In addition, in each of the operations, it is determined by HPLC which is described in the item "(7) Suppressing the evaluation of the GGA adsorption container", and it is determined that the content of the product is not reduced by the adsorption of the product. Sterile eye drops.

Sterilely filled in a transparent glass container (manufactured by Nippon Denshoku Chemical Co., Ltd.) having a capacity of 10 mL. These eye drops were subjected to a stability test in a container upright state after 7 days at 40 ° C and 75% RH. The content of teprenone (g/100 mL) in the eye drops at the time of post-production and after 7 days of standing was quantified under the HPLC conditions of the above conditions, and each residual ratio (%) was calculated.

The GGA-containing ophthalmic composition is prepared by formulating a prostaglandin-based latanoprost, a sympathetic β-blocking agent, timolol, or a ROCK inhibitor, fasudil hydrochloride. Significantly increase the residual rate of GGA. Therefore, it can be seen that the stability of GGA to heat is improved by the combination of latanoprost, timolol and fasudil hydrochloride.

(9) Evaluation of light stability of GGA

The ophthalmic agents containing teprenone, latanoprost, timolol and fasudil hydrochloride, respectively, were prepared as follows. The composition of each eyedrop is shown in Table 8.

Specifically, in the surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C, teprenone, or timolol, or fasudil hydrochloride, is added. After stirring in a hot water bath at 65 ° C for 2 minutes to dissolve, and then adding water at 65 ° C, the buffers were mixed and stirred to form a homogeneous solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide. This solution was filtered using a filter membrane having a pore size of 0.2 μm (Bottle Top Filter manufactured by Thermo Fisher Scientific Japan Co., Ltd.) to prepare a clarified sterile eye drop. In addition, in each of the operations, it was determined by HPLC, which will be described later, that the content of the GGA was not adsorbed on the device or the like, and the content of the eyedrop was reduced.

The eyedrops prepared by this method were aseptically filled in a container made of polyethylene terephthalate (Rohto Pharmaceutical Co., Ltd., Rohto Dry Aid EX container; capacity: about 8 mL). Irradiation of light to each eyedrop under the following conditions, and quantifying the content of teprenone in the sample at the time of manufacture and after irradiation, Residual rate (%).

Irradiation device: LTL-200A-15WCD (manufactured by Nagano Scientific Equipment Co., Ltd.)

Light source: D-65 tube

Total exposure: 1.3 million lx‧h (4000lx×325 hours)

Temperature and humidity: 25 ° C, 60% RH

Direction of light illumination: illuminated by the container in an upright position on the machine turntable

The GGA-containing ophthalmic composition is prepared by formulating a prostaglandin-based latanoprost, a sympathetic β-blocking agent, timolol, or a ROCK inhibitor, fasudil hydrochloride. Significantly increase the residual rate of GGA. Therefore, it can be seen that the stability of GGA to light can be improved by the combination of latanoprost, timolol and fasudil hydrochloride, and fasudil hydrochloride.

(industrial availability)

The ophthalmic preparation of the present invention is excellent in prevention, amelioration, or therapeutic effect of retinopathy, and suppresses conjunctival hyperemia and/or corneal damage which are side effects of a therapeutic agent for retinopathy other than GGA, and thus is a preparation which can be safely used after long-term use. .

At the same time, the ophthalmic preparation of the present invention is excellent in clarity, and it is very advantageous in ophthalmic preparations, such as inhibition of GGA adsorption in a container and excellent stability of light to GGA.

The drawings in this case are all experimental data and are not sufficient to represent the case.

Claims (19)

An ophthalmic preparation comprising (a) geranylgeranylacetone, and (b) a therapeutic agent for retinopathy (however, other than geranylgeranylacetone). The ophthalmic preparation according to claim 1, wherein the therapeutic agent for retinopathy (other than the geranylgeranylacetone) is selected from the group consisting of a prostaglandin agent and a sympatholytic agent. Sympathetic nerve stimulating agent, parasympathetic nerve stimulating agent, carbonic anhydrase inhibitor, ROCK inhibitor, calcium antagonist, EP2 promoter, adenosine A2a receptor agonist, VEGF aptamer, and VEGF inhibitor One or more of the groups. The ophthalmic preparation according to claim 1, which is a prophylactic, ameliorating, or therapeutic user of retinopathy. The ophthalmic preparation according to claim 3, wherein the retinopathy is selected from the group consisting of glaucoma, retinitis pigmentosa, senile macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular degeneration, hypertension Retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tears, retinal ruptures, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented venous retinal choroidal atrophy, convoluted chorioretinal atrophy, no choroidal malformation, crystalline Retinopathy, white spot retinitis, cone dystrophy, central halo choroidal atrophy, multiple British cellular retinal dystrophy, yolk-like macular dystrophy, macular cystic edema, occult macular dystrophy, Sturgeon, Retinal schizophrenia, central serous chorioretinopathy, spinal cerebellar atrophy type 7, familial exudative vitreoretinopathy, severe small cone cell syndrome, retinal vascular pattern, somatic chromosome dominant optic atrophy, body chromosome display More than one type of lesions in the group of sexual choroidal drusen, acute banded retinal epithelial lesions, tumor-induced retinopathy, photodamage, and ischemic retinopathy. The ophthalmic preparation according to claim 1, wherein the ophthalmic preparation, the intraocular injection, the ophthalmic ointment, the eye wash, the contact lens assembly solution, the contact lens solution, the corneal extraction ocular tissue preservation agent for transplantation, Infusion solution, sustained release intraocular implant, or sustained release contact lens preparation during surgery. The ophthalmic preparation according to claim 1, which is an aqueous composition or an oily composition. The ophthalmic preparation according to claim 1, which is in the form of a liquid, a fluid, a gel, or a semi-solid. The ophthalmic preparation according to claim 1, wherein the therapeutic agent for retinopathy (other than geranylgeranylacetone) causes conjunctival hyperemia and/or damage to the cornea. Suppressed. The ophthalmic preparation according to claim 1, wherein the adsorption of the geranylgeranylacetone to the container is inhibited. The ophthalmic preparation described in the first aspect of the patent application is inhibited by white turbidity. According to the ophthalmic preparation described in the first aspect of the patent application, the stability of heat and/or light of the geranylgeranylacetone is improved. The ophthalmic preparation according to the first aspect of the invention, which contains 0.00001 to 90% by weight of geranylgeranylacetone relative to the total amount of the preparation. The ophthalmic preparation according to claim 1, wherein the retinopathy therapeutic agent (other than the geranylgeranylacetone) is contained in an amount of 0.00001 to 90% by weight based on the total amount of the preparation. The ophthalmic preparation according to claim 1, wherein the anti-retinopathy therapeutic agent is contained in an amount of 0.0001 to 100,000 parts by weight based on 1 part by weight of the geranylgeranylacetone (however, it is a geranyl-based geranyl group). Other than acetone). The ophthalmic preparation according to claim 1, wherein the geranylgeranylacetone and the therapeutic agent for retinopathy (other than the geranylgeranylacetone) are contained in the same composition. The compounding agent of the substance, or the geranylgeranylacetone, is contained in a combined preparation of the individual compositions. A method for imparting an effect of inhibiting conjunctival hyperemia and/or corneal damage to an ophthalmic composition by using (a) geranylgeranylacetone and (b) retinopathy therapeutic agent in an ophthalmic composition (but Concomitant coexistence of geranyl-based geranylacetone, and the ophthalmic composition is used to inhibit (b) retinopathy therapeutic agent (however, other than geranylgeranylacetone) and/or conjunctival hyperemia and/or Or the role of corneal damage. A method for inhibiting white turbidity of an ophthalmic composition by using (a) geranylgeranylacetone and (b) retinopathy therapeutic agent in an ophthalmic composition (however, it is a geranyl geranyl group) Coexistence of other than acetone, and inhibiting the white turbidity of the ophthalmic composition. A method for inhibiting adsorption of geranyl-based geranyl-based acetone in a container by using (a) geranylgeranylacetone and (b) retinopathy therapeutic agent (but, geranium) Coexistence of geranyl-based acetone, while inhibiting the adsorption of geranylgeranyl-based acetone in the container. A method for improving the heat and/or light stability of geranyl-based geranyl-based acetone by using (a) geranylgeranylacetone and (b) retinopathy therapeutic agent for ophthalmic compositions (However, other than geranylgeranylacetone) coexist, and the stability of heat and/or light of geranylgeranylacetone is improved.