TW201542198A - Preventing, improving or treating agent for retina disease - Google Patents

Abstract

Provided is a preventing, improving or treating agent for retina disease, comprising geranylgeranylacetone 0.00001 to 95 weight %, wherein the geranylgeranylacetone is a geometrical isomer mixture containing (a) only one specific geranylgeranylacetone geometrical isomer, or (b) one specific geranylgeranylacetone geometrical isomer being equal to or more than 80 weight %, and having a great effect on preventing, improving or treating retina disease.

Description

Prevention, improvement or treatment of retinal diseases

The present invention relates to a prophylactic, ameliorating or therapeutic agent for retinal diseases.

Teprenone (eisai Co., Ltd.) is a mixture of 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetone in a weight ratio of 3:2. Teprenone is widely used as a therapeutic agent for peptic ulcer for oral administration.

Moreover, there is also a proposal to use teprenone in the ophthalmology field. For example, Patent Document 1 teaches that teprenone is used as an active ingredient of a preventive or therapeutic agent for dry eye, eye fatigue or dry eyes. Further, Patent Document 2 discloses an eyedrop containing clarification of teprenone, a phospholipid, a synthetic surfactant, and water.

Further, it is known that a cis-trans isomer is useful as an active ingredient of a therapeutic agent for retinal diseases than an unspecified geranylgeranylacetone (manufactured by Eisai Co., Ltd.).

For example, in Patent Document 3, a patient who is suffering from an eye disease such as diabetic retinopathy or glaucoma is administered with geranylgeranylacetone to make the heat of the eye tissue The performance or activity of a shock protein is increased, and the ocular tissue is supplemented with stem cells to improve the eye disease.

Further, in Non-Patent Document 1, it is taught that when an animal introduced into a retinal detachment is intraperitoneally administered with geranylgeranylacetone, the expression of heat shock protein 70 is induced, and apoptosis of visual cells is remarkably reduced.

Further, in Non-Patent Document 2, it is taught that when a glaucoma model rat is administered intraperitoneally with geranylgeranylacetone, the expression of heat shock protein 72 is induced, the retinal ganglion cell necrosis is reduced, and the optic nerve disorder is improved.

Further, in Non-Patent Document 3, it is taught that mice which are subjected to visual cell damage by light irradiation are orally administered with geranylgeranylacetone to induce thioredoxin and heat shock protein 72 in the retinal pigment epithelium. . Moreover, it has been suggested that the release of sulphur redox protein from the retinal pigment epithelium plays an important role in maintaining the visual cell line, indicating that geranylgeranylacetone plays a role in protecting visual cells by photodamage.

Further, in Non-Patent Document 4, it is taught that when a mouse which is administered with ischemia-induced retinal damage is orally administered with geranylgeranylacetone, the number of retinal nerves is significantly increased, and geranylgeranylacetone is Treatment of retinal disorders associated with ischemia is useful.

Further, in Non-Patent Document 5, it is taught that when a mouse with a multiple sclerosis model is orally administered with geranylgeranylacetone, the visual function is improved, the number of axons of the optic nerve is reduced, and the number of ganglion cells is suppressed.

Teprenone sold by eisai Co., Ltd. in the market, containing 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetone in a weight ratio of 3:2 ( WO2004/047822, Japan Special Japanese Patent No. 9-169639, Japanese Patent No. 4621326, Japanese Patent Laid-Open No. 2006-89393, No. 16 corrected Japanese Pharmacopoeia, attached document (Selbex). Therefore, the geranylgeranylacetone described in Patent Document 3 and Non-Patent Documents 1 to 5 contains 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranium in a weight ratio of 3:2. Basil-based acetone. In addition, commercially available teprenone other than eisai Co., Ltd. also contains 5E, 9E, 13E geranylgeranylacetone and 5Z,9E,13E geranylgeranylacetone in a weight ratio of 3:2. (such as the reagent MSDS (202-15733); and pure medicine).

However, the effect of improving the retinal disease by using 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetate in a weight ratio of 3:2 is practical. insufficient.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 8-133967

[Patent Document 2] Japanese Patent Laid-Open No. 2000-319170

[Patent Document 3] Japanese Special Open 2009-507770

[Non-patent literature]

[Non-Patent Document 1] The American Journal of Pathology, Vol.178, No.3, March 2011, 1080-1090

[Non-Patent Document 2] Investigative Ophthalmology & Visual Science, May 2003, Vol.44, No. 5, 1982-1992

[Non-Patent Document 3] The Journal of Neuroscience, March 2, 2005, 25(9), 2396-2404

[Non-Patent Document 4] Molecular vision, 2007, 13, 1601-1607

[Non-Patent Document 5] Neuroscience Letters, 462, 2009, 281-285

An object of the present invention is to provide a preventive, ameliorating or therapeutic agent for retinal diseases which is sufficiently effective in practical use.

In order to solve the above problems, the inventors of the present invention conducted intensive studies and found that only one of the GGA geometric isomers which are geranylgeranylacetone (hereinafter also referred to as "GGA") or GGA geometry is included. A mixture of isomers containing more than 80% by weight of a specific GGA geometric isomer has excellent retinal cell protection, and it is found that by inducing neurite elongation, cell function is enhanced, and prevention, improvement or treatment of retinal diseases is achieved.

Further, it has been found that the higher the ratio of the specific geometric isomers in the geometric mixture containing more than 80% by weight of the specific GGA geometric isomer, that is, the closer to the pure product, the prevention, improvement or treatment of retinal diseases. The stronger the effect.

The present invention has been completed based on the above findings, and provides a prophylactic, ameliorating or therapeutic agent for retinal diseases as described below.

Item 1 A prophylactic, ameliorating or therapeutic agent for retinal diseases, which comprises 0.00001 to 95% by weight of geranylgeranylacetone, and the geranylgeranylacetone is

(a) only one specific geranylgeranyl azide geometric isomer, or (b) a geranyl geranium containing a specific one of the geranylgeranylacetone geometric isomers of 80% by weight or more A mixture of base acetone geometric isomers.

The prophylactic, ameliorating or therapeutic agent for retinal diseases according to Item 1, wherein the specific one of the geranylgeranyl acetone geometric isomers is 5Z, 9E, 13E geranylgeranyl Acetone, 5E, 9Z, 13E geranylgeranylacetone or 5E, 9E, 13Z geranylgeranylacetone.

The prophylactic, ameliorating or therapeutic agent for retinal diseases according to the item 2, wherein the specific one of the geranylgeranyl acetone geometric isomers is 5Z, 9E, 13E geranylgeranyl acetone.

The prophylactic, ameliorating or therapeutic agent for retinal diseases according to Item 3, wherein the mixture of the geranylgeranylacetone geometric isomers of (b) is a geranium-containing geranium containing 5Z, 9E, 13E. A mixture of 5Z, 9E, 13E geranylgeranylacetone and 5E, 9E, 13E geranylgeranylacetone of 80% by weight or more of acetone.

The prophylactic, ameliorating or therapeutic agent for retinal diseases according to any one of the items 1 to 4, which is an ophthalmic preparation.

The preventive, ameliorating or therapeutic agent for retinal diseases according to any one of the items 1 to 4, which is an internal preparation.

The prophylactic, ameliorating or therapeutic agent for retinal diseases according to any one of the items 1 to 6, wherein the retinal disease is one or more selected from the group consisting of glaucoma, retinitis pigmentosa, and age-related macular degeneration , diabetic retinopathy, retinal detachment, diabetic macular degeneration, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tears, Retinal hole, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented venous retinal choroidal atrophy, cerebral gyrus retinal choroidal atrophy, choroid, crystal retinopathy, white spot retinopathy, cone cell malnutrition, Central halo-like choroidal dystrophy, doyne honeycomb retinal dystrophy, yolk-like macular dystrophy, cystic macular edema, cryptogenic macular dystrophy, Stargardt disease , retinal sepsis, central serous retinal choroidosis, spinal cord cerebellar disorder type 7, familial exudative vitreoretinosis, short-wave sensitive cone-enhanced syndrome (enhanced s-cone syndrome), retinal vascular-like streak , dominant hereditary optic atrophy, dominant genetic seizure (autosomal dominant drusen), acute banded cryptic outer retinopathy, cancerous retinopathy, photodamage and ischemic retinopathy.

Item 8. Use of a composition for the manufacture of a prophylactic, ameliorating or therapeutic agent for retinal diseases, which comprises geranylgeranylacetone 0.00001 to 95% by weight, the geranyl geranyl group Acetone

(a) only one specific geranylgeranyl azide geometric isomer, or (b) a geranyl geranium containing a specific one of the geranylgeranylacetone geometric isomers of 80% by weight or more A mixture of base acetone geometric isomers.

Item 9. A composition for preventing, ameliorating or treating a retinal disease, the composition comprising geranylgeranylacetone 0.00001 to 95% by weight, the geranylgeranylacetone is

(a) only one specific geranylgeranyl acetone geometric isomer, or (b) contains a specific one of the geranylgeranyl acetone geometric isomers 80 A mixture of geranylgeranylacetone geometric isomers of more than 5% by weight.

Item 10. A method for preventing, ameliorating or treating a retinal disease, which is a composition for administering a retinal disease, the composition comprising geranylgeranylacetone of 0.00001 to 95% by weight, the geranyl geranyl group Acetone

(a) only one specific geranylgeranyl azide geometric isomer, or (b) a geranyl geranium containing a specific one of the geranylgeranylacetone geometric isomers of 80% by weight or more A mixture of base acetone geometric isomers.

The agent of the present invention having a specific GGA geometric isomer or a GGA geometric isomer mixture containing 80% by weight or more of a specific GGA geometric isomer as an active ingredient, due to lesions, disorders or withering Death protects various retinal cells and significantly promotes their survival. Therefore, it has shown remarkable results in preventing, improving or treating various retinal diseases. Further, since the agent of the present invention promotes the function of the retinal cells by inducing or even promoting the elongation of the cell neurite, and regenerating the cells subjected to the disorder, it can be treated fundamentally. Moreover, the agent of the present invention can also enhance the function of cells that are not affected by inducing neurite elongation. Further, the agent of the present invention inhibits inflammation in the retina by inhibiting the production of inflammatory cytokines from retinal cells.

Further, since GGA is a drug which can be widely used and has been established to be safe, the agent of the present invention is a safe agent.

Further, since the agent of the present invention is a preparation which can be easily used at home in a patient such as an eye drop or an internal preparation, it is generally useful as a prophylactic, ameliorating and therapeutic agent for severe retinal diseases.

Fig. 1 is a view showing the action of protecting cells from hypoxia and low glucose-induced ischemia-like cell necrosis by GGA.

Fig. 2 is a graph showing the induction of neurite elongation by GGA in rat RGC.

Fig. 3 is a photograph showing the induction of neurite elongation by GGA in rat RGC.

Fig. 4 is a graph showing the induction of neurite elongation by GGA in rat RGC.

Fig. 5 is a view showing the action of protecting cells from oxidative stress by GGA.

Fig. 6 is a graph showing the effect of inhibiting IL-8 production by TNF-α of GGA.

Figure 7 is a graph showing the effect of NMDA-induced ocular nerves in glaucoma model rats by the all-trans body and the 5Z mono-cis body.

Fig. 8 is a graph showing the action of the ocular nerves of the glaucoma model rats induced by all-transformation protection of NMDA.

Fig. 9 is a graph showing that the all-trans form causes an increase in the thickness of the intraretinal reticular layer of the NMDA-induced glaucoma model rat.

Fig. 10 is a graph showing the action of the ocular nerves of the glaucoma model rats induced by all-transformation protection of NMDA.

Hereinafter, the present invention will be described in detail.

The prophylactic, ameliorating or therapeutic agent for retinal diseases of the present invention contains a specific GGA geometric isomer or a GGA geometric isomer mixture containing 80% by weight or more of a specific GGA geometric isomer as an active ingredient. .

Geranyl geranylacetone (1) Types of geometric isomers

GGA has eight geometric isomers. Specifically: (5E, 9E, 13E)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5E, 9E, 13EGGA) ( All-trans), (5Z, 9E, 13E)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5Z,9E,13EGGA) (5Z monocis type), (5Z, 9Z, 13E)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5Z, 9Z, 13EGGA) (13E SLR) (5Z, 9Z, 13Z)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5Z, 9Z, 13ZGGA) (trans-cis), (5E, 9Z, 13E)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5E, 9Z , 13EGGA) (9Z monocis type), (5E, 9Z, 13Z)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2-one (5E , 9Z, 13ZGGA) (5E SLR) (5E, 9E, 13Z)-6,10,14,18-Tetramethyl-5,9,13,17-non-tetradecen-2-one (5E , 9E, 13ZGGA) (13Z monocis type), and (5Z, 9E, 13Z)-6,10,14,18-tetramethyl-5,9,13,17-non-tetradecen-2- There are 8 kinds of ketone (5Z, 9E, 13ZGGA) (9E single-antibody).

Further, the 5Z single-cis, 9Z single-cis, and 13Z single-cis are also referred to as single-cis GGA.

In the present invention, a specific one of the GGA geometric isomers may be any of the above eight geometric isomers. Hereinafter, a specific GGA geometric isomer is also simply referred to as "specific GGA geometric isomer".

Further, the mixture containing a specific GGA geometric isomer may be contained in an amount of 80% by weight or more based on any one of the above eight geometric isomers. The specific geometric isomer at this time is preferably a 5Z single cis, a 9Z single cis or a 13Z single cis single cis GGA, more preferably a 5Z single cis. Moreover, it is preferred to exclude a mixture of geometric isomers containing more than 80% by weight of the total trans form.

When the active ingredient is a mixture containing 80% by weight or more of a specific GGA geometric isomer, the other GGA geometric isomers may be any of the remaining 7 geometric isomers after the exclusion of the all-trans form. Further, one type or two or more types of other GGA geometric isomers may be used.

The GGA geometric isomer mixture preferably contains a mixture of a mono-cis and a trans-trans form of 80% by weight or more of a single cis form, and more preferably a 5Z mono-supplement containing more than 80% by weight of a 5Z single cis form. a mixture of a body and an all-trans body.

The ratio of the specific geometric isomer in the GGA geometric isomer mixture is 80% by weight or more, preferably 82% by weight or more, more preferably 84% by weight or more, still more preferably 86% by weight or more, and still more Preferably, it is 88% by weight or more, more preferably 90% by weight or more, and even more preferably 92% by weight. More preferably, the amount is more than 94% by weight, more preferably 96% by weight or more, still more preferably 98% by weight or more, still more preferably 99% by weight or more. As long as it is in the above range, it is remarkable in the prevention, improvement or treatment of retinal diseases.

(2) Method for producing GGA geometric isomer <All-trans-body>

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

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

Further, commercially available teprenone (eisai Co., Ltd., Wako Pure Chemical Industries, Yangjintang) can also be obtained by using, for example, a mobile phase of n-hexane:ethyl acetate=9:1 gel chromatography. 5Z single cis isomer separation. Separation of the 5Z monocis form of the commercially available teprenone with the all-trans form can also be carried out, for example, by entrusting the Kobe Natural Products Chemical Company.

Further, the all-trans form can 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, a method represented by the following synthesis scheme is described.

Specifically, in the above reaction formula, the geranyl agar alcohol 1 Compound 2 and aluminum isopropoxide were mixed, and the mixture was slowly heated to 130 ° C to carry out a reaction. After completion of the reaction, the residue of Compound 2 was removed, and the reaction mixture was diluted with 5% sodium carbonate, and the residue of aluminum hydride was quenched. Thereby, an all-trans form is obtained. Further, the entire trans form may be purified by gel chromatography or the like using dichloromethane as an eluent.

<single cis type>

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

The 5Z monocis is obtained by separation of commercially available teprenone.

<Other>

Those of ordinary skill in the art to which the present invention pertains may also make other GGA geometric isomers by reference to the above methods.

Further, the geometric isomer mixture of GGA, for example, a mixture of an all-trans form and a 5Z single-cis form, and containing 80% by weight or more of the total trans form, can be obtained by commercially available teprenone. Add all-trans body to it. Further, it is a mixture of a 5Z single-cis form and a all-trans form, and contains a 5Z single-cis form of 80% by weight or more, which can be obtained by adding a 5Z single cis form to a commercially available teprenone. .

preparation

The dosage form of the preventive, ameliorating or therapeutic agent for retinal diseases of the present invention is not particularly limited, and for example, an ophthalmic agent, a nasal spray, an internal dose, an injection (intravenous injection, subcutaneous injection, intramuscular injection) can be used without limitation. Or a known pharmaceutical dosage form such as a percutaneous absorption agent, a suppository or an inhalation. Among them, in terms of a preventive, ameliorating or therapeutic effect of a retinal disease, and a dosage form which is easy for a patient to use, it is preferably an ophthalmic agent, a nasal spray, an internal preparation or a transdermal absorption agent, and more preferably an ophthalmic treatment. Agent.

Regardless of the dosage form employed, the preparation may contain, in addition to GGA, a pharmaceutically acceptable base or carrier, a pharmaceutically acceptable additive, and/or a physiologically active ingredient or a pharmacologically active ingredient other than GGA.

Regardless of the dosage form, the dosage form of the present invention is typically contained in a container or even a bag.

The content of GGA in the preventive, ameliorating or therapeutic agent of the retinal disease of the present invention is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, and still more preferably 0.0001% by weight, based on the total amount of the preparation, regardless of the dosage form. The above is more preferably 0.0005 wt% or more, still more preferably 0.001 wt% or more. Further, it may be 0.005% by weight or more, may be 0.01% by weight or more, may be 0.05% by weight or more, may be 0.1% by weight or more, may be 0.5% by weight or more, and may be 1% by weight or more. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

Further, the content of GGA in the preventive, ameliorating or therapeutic agent of the retinal disease of the present invention is preferably 95% by weight or less, more preferably 90% by weight or less, still more preferably 80% by weight or less, based on the total amount of the ophthalmic agent. . Further, it may be 75% by weight or less, 70% by weight or less, 65% by weight or less, 60% by weight or less, 55% by weight or less, 50% by weight or less, or 45% by weight or less. , may be 40% by weight or less, may be 35% by weight or less, may be 30% by weight or less, and may be 25% by weight or less. The content may be 15% by weight or less, may be 10% by weight or less, or may be 5% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the prophylactic, ameliorating or therapeutic agent of the retinal disease of the present invention may be, for example, about 0.00001 to 95% by weight, about 0.00001 to 90% by weight, about 0.00001 to 80% by weight, and about 0.00001 to the total amount of the composition. 75 wt%, about 0.00001 to 70 wt%, about 0.00001 to 65 wt%, about 0.00001 to 60 wt%, about 0.00001 to 55 wt%, about 0.00001 to 50 wt%, about 0.00001 to 45 wt%, about 0.00001 to 40 wt% % by weight, about 0.00001 to 35% by weight, about 0.00001 to 30% by weight, about 0.00001 to 25% by weight, about 0.00001 to 20% by weight, about 0.00001 to 15% by weight, about 0.00001 to 10% by weight, about 0.00001 to 5 by weight. %, about 0.00005 to 95% by weight, about 0.00005 to 90% by weight, about 0.00005 to 80% by weight, about 0.00005 to 75% by weight, about 0.00005 to 70% by weight, about 0.00005 to 65% by weight, about 0.00005 to 60% by weight , about 0.00005 to 55% by weight, about 0.00005 to 50% by weight, about 0.00005 to 45% by weight, about 0.00005 to 40% by weight, about 0.00005 to 35% by weight, about 0.00005 to 30% by weight, about 0.00005 to 25% by weight, About 0.00005 to 20% by weight, about 0.00005 to 15% by weight, about 0.00005 to 10% by weight, about 0.00005 to 5 %, about 0.0001 to 95% by weight, about 0.0001 to 90% by weight, about 0.0001 to 80% by weight, about 0.0001 to 75% by weight, about 0.0001 to 70% by weight, about 0.0001 to 65% by weight, about 0.0001 to 60% by weight %, about 0.0001 to 55% by weight, about 0.0001 to 50% by weight, about 0.0001 Up to 45% by weight, about 0.0001 to 40% by weight, about 0.0001 to 35% by weight, about 0.0001 to 30% by weight, about 0.0001 to 25% by weight, about 0.0001 to 20% by weight, about 0.0001 to 15% by weight, about 0.0001 to 10% by weight, about 0.0001 to 5% by weight, about 0.0005 to 95% by weight, about 0.0005 to 90% by weight, about 0.0005 to 80% by weight, about 0.0005 to 75% by weight, about 0.0005 to 70% by weight, about 0.0005 to 65% by weight % by weight, about 0.0005 to 60% by weight, about 0.0005 to 55% by weight, about 0.0005 to 50% by weight, about 0.0005 to 45% by weight, about 0.0005 to 40% by weight, about 0.0005 to 35% by weight, about 0.0005 to 30% by weight %, about 0.0005 to 25% by weight, about 0.0005 to 20% by weight, about 0.0005 to 15% by weight, about 0.0005 to 10% by weight, about 0.0005 to 5% by weight, about 0.001 to 95% by weight, about 0.001 to 90% by weight , about 0.001 to 80% by weight, about 0.001 to 75% by weight, about 0.001 to 70% by weight, about 0.001 to 65% by weight, about 0.001 to 60% by weight, about 0.001 to 55% by weight, about 0.001 to 50% by weight, From about 0.001 to 45% by weight, from about 0.001 to 40% by weight, from about 0.001 to 35% by weight, from about 0.001 to 30% by weight, from about 0.001 to 25% by weight, from about 0.001 to 20% by weight, from about 0.001 to 15% by weight %, about 0.001 to 10% by weight, about 0.001 to 5% by weight, about 0.005 to 95% by weight, about 0.005 to 90% by weight, about 0.005 to 80% by weight, about 0.005 to 75% by weight, about 0.005 to 70% by weight , from about 0.005 to 65% by weight, from about 0.005 to 60% by weight, from about 0.005 to 55% by weight, from about 0.005 to 50% by weight, from about 0.005 to 45% by weight, from about 0.005 to 40% by weight, from about 0.005 to 35% by weight, About 0.005 to 30% by weight, about 0.005 to 25% by weight, about 0.005 to 20% by weight, about 0.005 to 15 % by weight, about 0.005 to 10% by weight, about 0.005 to 5% by weight, about 0.01 to 95% by weight, about 0.01 to 90% by weight, about 0.01 to 80% by weight, about 0.01 to 75% by weight, about 0.01 to 70% by weight %, about 0.01 to 65% by weight, about 0.01 to 60% by weight, about 0.01 to 55% by weight, about 0.01 to 50% by weight, about 0.01 to 45% by weight, about 0.01 to 40% by weight, about 0.01 to 35% by weight , about 0.01 to 30% by weight, about 0.01 to 25% by weight, about 0.01 to 20% by weight, about 0.01 to 15% by weight, about 0.01 to 10% by weight, about 0.01 to 5% by weight, about 0.05 to 95% by weight, About 0.05 to 90% by weight, about 0.05 to 80% by weight, about 0.05 to 75% by weight, about 0.05 to 70% by weight, about 0.05 to 65% by weight, about 0.05 to 60% by weight, about 0.05 to 55% by weight, about 0.05 to 50% by weight, about 0.05 to 45% by weight, about 0.05 to 40% by weight, about 0.05 to 35% by weight, about 0.05 to 30% by weight, about 0.05 to 25% by weight, about 0.05 to 20% by weight, about 0.05 Up to 15% by weight, about 0.05 to 10% by weight, about 0.05 to 5% by weight, about 0.1 to 95% by weight, about 0.1 to 90% by weight, about 0.1 to 80% by weight, about 0.1 to 75% by weight, about 0.1 to 70% by weight, about 0.1 to 65% by weight, about 0.1 to 60% by weight, about 0.1% 55 wt%, about 0.1 to 50 wt%, about 0.1 to 45 wt%, about 0.1 to 40 wt%, about 0.1 to 35 wt%, about 0.1 to 30 wt%, about 0.1 to 25 wt%, about 0.1 to 20 wt% % by weight, about 0.1 to 15% by weight, about 0.1 to 10% by weight, about 0.1 to 5% by weight, about 0.5 to 95% by weight, about 0.5 to 90% by weight, about 0.5 to 80% by weight, about 0.5 to 75 parts by weight %, about 0.5 to 70% by weight, about 0.5 to 65% by weight, about 0.5 to 60% by weight, about 0.5 to 55% by weight, about 0.5 to 50% by weight, about 0.5 to 45% by weight, about 0.5 to 40% by weight, about 0.5 to 35% by weight, about 0.5 to 30% by weight, about 0.5 to 25% by weight, about 0.5 to 20% by weight, about 0.5 to 15% by weight, about 0.5 to 10% by weight % by weight, about 0.5 to 5% by weight, about 1 to 95% by weight, about 1 to 90% by weight, about 1 to 80% by weight, about 1 to 75% by weight, about 1 to 70% by weight, about 1 to 65 parts by weight %, about 1 to 60% by weight, about 1 to 55% by weight, about 1 to 50% by weight, about 1 to 45% by weight, about 1 to 40% by weight, about 1 to 35% by weight, about 1 to 30% by weight From about 1 to 25% by weight, from about 1 to 20% by weight, from about 1 to 15% by weight, from about 1 to 10% by weight, from about 1 to 5% by weight.

(1) Ophthalmic agent

The properties of the ophthalmic preparation are not particularly limited, and may be, for example, a liquid, a fluid, a gel, a semi-solid or a solid. Further, it is also included in the preparation of a semi-liquid, a fluid, a gel, a semi-solid or a solid by preparation. Solid form means, for example, an ointment having a plasticity property which is deformable by application of stress.

The type of ophthalmic preparation is not particularly limited. For example, eye drops (including eye drops when using contact lenses), eye wash, contact lens solution, contact lens solution (washing solution, preservation solution, disinfectant, multifunctional solution, package) Liquid), a preservation agent for eye tissue extracted from a cornea for transplantation, a perfusate for surgery, an ophthalmic ointment (water-soluble ophthalmic ointment, an oil-soluble ophthalmic ointment), an intraocular injection (for example, an intravitreal injection), and a solution Release intraocular implants and sustained release contact lens preparations. From the viewpoint of good transferability to the affected part, it is preferably an eye drop, an intraocular injection, an ophthalmic ointment and an eye wash, and more preferably an eye drop.

Further, the ophthalmic agent may be an aqueous composition (as a base or carrier, mainly containing water or even hydrophilic), or an oily composition (as a base or carrier, mainly containing oily or hydrophobic).

In the case of the aqueous composition, the water content is preferably 50% by weight or more, more preferably 75% by weight or more, still more preferably 90% by weight or more based on the total amount of the preparation. Also, the base or carrier may consist solely of water.

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

Modulation methods for ophthalmic preparations are conventional. Additives and other active ingredients (physiologically active ingredients or pharmacologically active ingredients other than GGA) may be prepared by mixing a GGA geometric isomer mixture with a pharmaceutically acceptable base or carrier, and optionally with a pharmaceutically acceptable ophthalmic preparation. ) mixed and modulated.

<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 and the like. The base or carrier for the intraocular injection can be exemplified by distilled water for injection or physiological saline.

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

<additive>

Examples of the additive include 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, a thickener, and the like. . Intraocular injections may also contain a cosolvent, a suspending agent, an isotonic agent, a buffer, and a painless Agents, stabilizers and preservatives.

The additive may be used alone or in combination of two or more.

Specific examples of the additives are exemplified below.

Surfactant: for example, polyoxyethylene (hereinafter also referred to as "POE")-polyoxypropylene (hereinafter also referred to as "POP") block copolymer (for example, Poloxamer 407, Poloxamer 235, Poloxamer 188), POE-POP of ethylenediamine Block copolymer adducts (eg, poloxamine, POE sorbitan fatty acid esters (eg, polysorbate 20, polysorbate 60, polysorbate 80 (TO-10, etc.)) , POE hardened castor oil (such as POE (60) hardened castor oil (HCO-60, etc.)), POE castor oil, POE alkyl ether (such as polyoxyethylene (9) lauryl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether) and a nonionic surfactant of polyoxyl stearate; such as a glycine type amphoteric surfactant (for example, alkyldiaminoethylglycine, alkylpolyamine Amphoteric surfactants of ethylglycolic acid and betaine type amphoteric surfactants (eg, lauryl dimethylaminoacetic acid betaine, imidazolinium betaine) and alkyl 4-grade ammonium salts (eg, benzalkonium chloride) a benzylic ammonium chloride) cationic surfactant or the like.

Also, the number in parentheses indicates the addition of the number of moles.

Perfume or cooling agent: for example: camphor, borneol, terpenes (these may be any of d, l or dl), mint water, eucalyptus oil, bergamot oil, fennel, Essential oils such as eugenol, geraniol, menthol, limonene, peppermint oil, peppermint oil and rose oil.

Preservatives, bactericides or antibacterial agents: for example, polidronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride (benzalkonium chloride) Benzethonium chloride), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate , butyl paraben, hydroxyquinoline sulfate, phenylethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride), and 谷洛奇 (transliteration, (trade name)) (manufactured by Rhodia Co., Ltd.).

The pH adjusting agent is, for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid or the like.

Isotonic agent: for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, hydrogen phosphate Disodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin and propylene glycol.

Chelating agents: for example, ascorbic acid, tetrasodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, citric acid, and the like.

Buffering agent: 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; a carbonate buffer such as sodium hydrogencarbonate or sodium carbonate; such as boric acid, borax Boric acid buffer; such as taurine, aspartic acid and its salts (potassium salt, etc.), ε-aminocaproic acid, amino acid buffer, and the like.

Among them, it is preferred to adjust the pH using a phosphate buffer, thereby suppressing the adsorption of GGA on the container wall, thereby suppressing the GGA in the composition. The content rate is lowered. Further, it is possible to suppress the white turbidity at the time of low-temperature storage, and to suppress the adsorption of GGA on the contact lens, and the effect on the stability of heat and light is good.

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

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

Among them, it is preferred to use at least one selected from the group consisting of alkali metal salts of phosphoric acid and phosphoric acid, and more preferably at least one group selected from the group consisting of sodium phosphates of phosphoric acid and phosphoric acid.

Preferred combinations of the phosphate buffer include phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, disodium hydrogen phosphate, and phosphoric acid. Combination of trisodium, combination of phosphoric acid, sodium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, phosphoric acid, disodium hydrogen phosphate, phosphoric acid, sodium dihydrogen phosphate Combination, a combination of phosphoric acid, trisodium phosphate, a combination of disodium hydrogen phosphate, sodium dihydrogen phosphate, a combination of disodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate, and trisodium phosphate.

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

The content of the phosphate buffer is converted to an anhydride in terms of the total amount of the ophthalmic agent, preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, still more preferably 0.05% by weight. %the above. When the phosphate buffer is added in the above range, the effect of sufficiently calming the GGA, the effect of suppressing low-temperature white turbidity, and the effect of inhibiting the adsorption of GGA on the container wall and the contact lens can be obtained.

Further, the content of the phosphate buffer in the ophthalmic preparation is preferably 10% by weight or less, more preferably 7% by weight or less, still more preferably 5% by weight or less, based on the total amount of the ophthalmic preparation. More preferably, it is 3% by weight or less. As long as it is in the above range, there is less irritation to the eyes.

The content of the phosphate buffer is converted to an anhydrate relative to the total amount of the ophthalmic agent, 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, or about 0.001 to 3% by weight, About 0.005 to 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, and about 0.05 to 3% by weight.

Further, the content of the phosphate buffer is preferably 0.0005 parts by weight or more, more preferably 0.001 parts by weight or more, still more preferably 0.005 parts by weight or more, still more preferably 0.01 parts by weight, based on 1 part by weight of the GGA. the above. As long as it is in the above range, by adding a phosphate buffer, sufficient GGA stabilization effect can be obtained, and the effect of suppressing low temperature white turbidity can be obtained. The effect of GGA adsorption on the container wall and contact lenses.

Further, the content of the phosphate buffer is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, still more preferably 500 parts by weight or less, still more preferably 200 parts by weight, based on 1 part by weight of the GGA. the following. As long as it is in the above range, the irritation to the eyes is small.

The content of the phosphate buffer in terms of 1 part by weight of GGA may be, as an anhydride, from about 0.0005 to 5000 parts by weight, from about 0.0005 to 1000 parts by weight, from about 0.0005 to 500 parts by weight, from about 0.0005 to 200 parts by weight, and from 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, about 0.005 to 200 parts by weight 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.

Stabilizing agent: trometamol, sodium formaldehyde sulfoxylate (rongalite), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate and glyceryl monostearate.

Antioxidant: ascorbic acid, ascorbic acid derivatives (ascorbic acid 2-sodium sulfate, sodium ascorbate, ascorbyl-2-phosphate, ascorbyl-2-phosphate, etc.), sodium bisulfite, sodium sulfite, sodium thiosulfate, etc. Antioxidants.

The ophthalmic agent can contain a fat-soluble antioxidant, whereby the ophthalmic agent can be inhibited from being adsorbed on the container wall, and the content of the GGA in the composition can be suppressed from being lowered. Moreover, it can inhibit the adsorption of GGA on contact lenses, and also enhance GGA's stability to heat and light.

The fat-soluble antioxidant may, for example, be a butyl group-containing phenol such as butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); such as ascorbyl palm Acid esters, ascorbyl stearate, ascorbyl phosphatidyl phosphate, ascorbyl phosphate tocopherol, ascorbyl triphosphate, ascorbyl phosphate ascorbyl ester; such as alpha-tocopherol, beta-tocopherol, gamma-tocopherol Tocopherols of δ-tocopherol; tocopherol derivatives such as tocopherol acetate, tocopherol nicotinic acid, tocopherol succinate; e.g. ethyl gallate, propyl gallate, octyl gallate, lauryl gallate Gallic acid ester; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; vegetable oil such as soybean oil, rapeseed oil, olive oil, sesame oil; such as lutein, shrimp red Carotenoids of astaxanthin; polyphenols such as anthocyanins, catechins, tannins, curcumin; retinol, retinol (retinyl acetate, retinyl acetate) Alcohol, butyric acid, retinol, octanoic acid Alcohol, retinyl laurate, retinyl stearate, retinyl myristic acid, retinol oleate, retinyl linolenate, retinol linoleic acid, retinyl palmitate, etc. , retinal, retinal (retinal acetate, retinyl propionate, retinal palmitate, etc.), retinoic acid (retinoic acid), retinyl ester (methyl retinoic acid) , retinoic acid ethyl ester, retinoic acid retinol ester, retinoic acid tocopherol, etc.), retinol dehydrogenate, retinal dehydrogenate, retinoic acid dehydrogenate, provitamin A (α- Carotene, β-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, echinenone, etc., vitamin A and other vitamin A; CoQ10 Wait. These compounds are sold in the market.

Among them, preferred are butyl phenol, NDGA, ascorbate, tocopherol, tocopherol derivative, gallic acid ester, propyl gallate and 3-butyl-4-hydroxyquinolin-2 ketone, vegetable oil, vitamin Class A. Among them, preferred are butyl-containing phenol, tocopherol, tocopherol derivative, vegetable oil, vitamin A, more preferably butyl-containing phenol, vegetable oil, retinol or retinol ester, and more preferably BHT. , BHA, sesame oil, retinyl palmitate.

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

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, still more preferably 0.0001% by weight or more, still more preferably 0.0005% by weight based on the total amount of the ophthalmic agent. %the above. As long as it is in the above range, by adding a fat-soluble antioxidant, it is possible to sufficiently suppress the effect of GGA adsorption on the container wall (the effect of suppressing the decrease in the GGA content), suppress the effect of GGA adsorption on the contact lens, and improve the heat and GGA. The effect of the stability of light.

Further, 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, still more preferably 2% by weight or less, and still more preferably 1 based on the total amount of the composition. Below weight%. As long as it is in the above range, there is less irritation to the eyes.

The content of the fat-soluble antioxidant in the ophthalmic agent 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, and about 0.00001 to 1% by weight, based on the total amount of the ophthalmic agent. 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 Up 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, about 0.0005 to 1% by weight.

Further, 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, still more preferably 0.005 part by weight or more, still more preferably 0.01% by weight based on 1 part by weight of the GGA. More than one. As long as it is in the above range, the effect of suppressing the adsorption of GGA on the container wall (the effect of suppressing the decrease in the GGA content), the effect of inhibiting the adsorption of GGA on the contact lens, and the improvement of the heat and light of the GGA can be obtained by adding a fat-soluble antioxidant. The effect of stability.

Further, the content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, still more preferably 10 parts by weight or less, still more preferably 5 parts by weight based on 1 part by weight of the GGA. The following. As long as it is in the above range, there is less irritation to the eyes.

The content of the fat-soluble antioxidant in the ophthalmic agent is, 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, about 0.0001 to 5 parts by weight, and about 0.001, based on 1 part by weight of the GGA. 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.

Thickeners: such as guar gum, hydroxypropyl guar, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl Cellulose-based polymer compound of cellulose, sodium carboxymethylcellulose; such as gum arabic, karaya gum, sanmon gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, heparin, Heparin, heparin sulfate, heparan sulfate, hyaluronic acid, hyaluronic acid (sodium salt, etc.), sodium chondroitin sulfate, starch, chitin and its derivatives, chitosan and its derivatives, carrageenan Polyethylene polymer compound of vegetable gum, sorbitol, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene methacrylate; alkali metal salt of polyacrylic acid (sodium salt and potassium salt), amine salt of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), carboxyvinyl polymer of ammonium polyacrylate; casein, gelatin, collagen, pectin, elastin, neural amine, liquid paraffin, glycerin, poly Ethylene glycol, polyvinyl diol (macrogol), polyethyleneimine alginate (sodium salt, etc.), alginate (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine.

<Other ingredients for preventing, improving or treating retinal diseases>

The ophthalmic agent may contain, in addition to GGA, a component that prevents or treats retinal diseases by a different action from GGA. That is, the ophthalmic agent preferably contains a combination of GGA and other ingredients as an active ingredient for preventing, ameliorating or treating retinal diseases. One component may be used alone or in combination of two or more kinds, which may be used for the prevention or treatment of retinal diseases.

The combination is not limited to the following, but for example, a combination of GGA and a prostaglandin agent (GGA and latanoprost, GGA and travoprost, GGA and fluoroprosthetic) Combination of GVA and prostaglandin F2 α derivatives (tafluprost, GGA and bimatoprost, etc.), combination of GGA and prostaglandin (GGA and isopropyl unoprostone) Such as GGA and beta blocker combination (GGA and timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA and coagulation Glued carteolol, etc., combination of GGA and β 1 blocker (GGA with Betaxolol hydrochloride, etc.), combination of GGA and α β blocker (GGA and levobunol hydrochloride) Levobunolol hydrochloride, GGA and nipradil, etc., combination of GGA and α 1 blocker (GGA and bunazol hydrochloride) (bunazosin hydrochloride, etc.) a combination of GGA and a sympathetic blocker; such as GGA and pilocarpine hydrochloride, GGA and distigmine bromide GGA and parasympathetic agonist; GGA combined with epinephrine, GGA and hydrogen epinephrine, GGA and dipivefrine hydrochloride, GGA and α 2 agonist (GGA and Brimonidine tartrate, etc.) Combination of GGA and sympathetic agonist; such as GGA and acetonitrile, GGA and dozolamide hydrochloride, GGA and brinzolamide GGA and carbonic anhydrase inhibitors Combinations such as GGA and fasudil hydrochloride, GGA and Y-27632, GGA and AR-12286, GGA and INS-117548, GGA and SNJ-1656, GGA and K-115 GGA and ROCK ( a combination of specific inhibitors of Rho-associated coiled coil forming protein kinase; such as GGA and Lomel Combination of GGA and calcium antagonist of lomerizine hydrochloride; such as GGA and DE-117 combination of GGA and EP2 agents; such as GGA and OPA-6566 combination of GGA and adenosine A2a receptor agonist Such as the combination of GGA and VEGF aptamer (GGA with pegaptanib sodium), GGA and VEGF inhibitor (GGA and Lanibizumab, GGA and Bay A combination of GGA of a single antibody (bevacizumab) and a therapeutic agent for age-related macular degeneration.

Among them, in terms of prevention, improvement, and treatment of retinal diseases, the combination of GGA and prostaglandin F2 α derivatives, and GGA and sympathetic block drugs (especially GGA and β) are preferred. Combination of blocking agents), combination of GGA and ROCK inhibitors, and combination of GGA and carbonic anhydrase inhibitors.

<Other pharmacologically active ingredients or physiologically active ingredients>

Further, the ophthalmic agent can be formulated with a pharmacologically active ingredient or a physiologically active ingredient other than the component for preventing, ameliorating or treating retinal diseases. These pharmacologically active ingredients or physiologically active ingredients may be used alone or in combination of two or more.

The pharmacologically active ingredients or physiologically active ingredients may also be exemplified by other examples such as a neurotrophic factor, a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine component or an antiallergic drug. Ingredients, vitamins, amino acids, antibacterial or bactericidal ingredients, sugars, high molecular compounds, cellulose or derivatives thereof, and local anesthetic ingredients. Specific examples of the agents are exemplified below.

Neurotrophic factor: neurotrophic factor (NGF:nerve Growth factor), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF).

Further, since the serum contains a nourishing factor represented by a neurotrophic factor, serum obtained from the patient may be added to prepare a preparation for the patient.

Decongestant components, such as alpha-adrenergic agents, specifically: adrenaline, epinephrine hydrochloride, ephedrine hydrochloride, hydroxyxazoline hydrochloride, tetrahydrozoline hydrochloride, naprazoline hydrochloride (naphazoline) Hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, hydrogen epinephrine tartrate and nepyrimidine nitrate. These may be any of d, l or dl.

Eye muscle regulating drug component: for example, a cholinesterase inhibitor having an active center similar to acetylcholine, specifically, methyl stearate neostigmine methylsulfate, tropicamide, civil engineering Helenien and atropine sulfate.

Anti-inflammatory drug component or astringent drug component: for example, zinc sulfate, zinc lactate, allantoin, ε-aminocaproic acid, Indomethacin, lysozyme chloride, silver nitrate, pranoprofen (pranoprofen), sodium sulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, diclofenac sodium, bromfenac sodium, berberine chloride, berberine sulfate, etc. .

Antihistamine or anti-allergic ingredients: for example, acitabanolast, diphenhydramine or its hydrochloride salt, chlorpheniramine maleate, Yanhu Ketotifen fumarate, levocabastine or its hydrochloride, amlexanox, ibudilast, tazanolast, trasin Salt such as tranilast, oxatomide, suplatast or its tosylate, sodium cromoglycate and pemimolast potassium.

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

Amino acids: for example, aminoethanesulfonic acid (taurine), glutamic acid, creatine lactam, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / Potassium 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 d, l or dl.

Antibacterial or bactericidal ingredients: for example, alkyl polyaminoethylglycine, chloramphenicol, sulfamethoxazole Sulfamethoxazole, sulfamethoxazole Sulfisoxazole, sulfamethoxazole Sulfamethoxazole sodium, sulfamethoxazole Oxazole diethanolamine, sulfonamide Oxazol monoethanolamine, sulfamethine Sulfasomezole sodium, sulfisomidine sodium, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride and 9-[ (2-hydroxyethoxy)methyl] acyclovir or the like.

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

High molecular compound: for example, alginic acid, sodium alginate, dextrin, dextran, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (complete or partial ketone), polyvinylpyrrolidone, carboxyvinyl polymer, Polyethylene glycol and its pharmaceutically acceptable salts and the like.

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

Local anesthetic components: for example, chlorobutanol, Procaine hydrochloride, Lidocaine hydrochloride, and the like.

<Content of GGA>

The content of GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, still more preferably 0.0001% by weight or more, still more preferably 0.0005% by weight or more, based on the total amount of the ophthalmic preparation. More preferably, it is 0.001% by weight or more. Further, it may be 0.005% by weight or more, may be 0.01% by weight or more, may be 0.05% by weight or more, may be 0.1% by weight or more, may be 0.5% by weight or more, and may be 1% by weight or more. As long as it is within the above range, sufficient prevention, improvement or treatment of retinal diseases can be obtained. The effect of the disease.

Further, the content of GGA in the ophthalmic preparation is preferably 90% by weight or less, more preferably 50% by weight or less, still more preferably 30% by weight or less based on the total amount of the ophthalmic preparation. Moreover, it may be 10% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the ophthalmic preparation relative to the total amount of the composition 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 0.00005 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 0.0001 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 % 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 0.01 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 0.05 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 0.1 to 90% by weight, about 0.1 to 50% by weight , about 0.1 to 30% by weight, about 0.1 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 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 particular, when the ophthalmic preparation is a preparation other than a solid preparation such as a liquid, a fluid, a gel, or a semisolid, the content of GGA in the preparation is preferably 10% by weight or less based on the total amount of the preparation. It is preferably 8% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less. It can also be 2% by weight or less.

When the ophthalmic preparation is a preparation other than a solid preparation such as a liquid, a fluid, a gel or a semi-solid, the content of the GGA in the ophthalmic composition may be, for example, about 0.00001 to 10 with respect to the total amount of the composition. % by weight, about 0.00001 to 8% by weight, about 0.00001 to 5% by weight, about 0.00001 to 3% by weight, about 0.00001 to 2% by weight, about 0.00005 to 10% by weight, about 0.00005 to 8% by weight, about 0.00005 to 5 by weight. %, about 0.00005 to 3% by weight, about 0.00005 to 2% by weight, about 0.0001 to 10% by weight, about 0.0001 to 8% by weight, about 0.0001 to 5% by weight, about 0.0001 to 3% by weight, about 0.0001 to 2% by weight , about 0.0005 to 10% by weight, about 0.0005 to 8% by weight, about 0.0005 to 5% by weight, about 0.0005 to 3% by weight, about 0.0005 to 2% by weight, about 0.001 to 10% by weight, about 0.001 to 8% by weight, About 0.001 to 5% by weight, about 0.001 to 3% by weight, about 0.001 to 2% by weight, about 0.005 to 10% by weight, about 0.005 to 8% by weight, about 0.005 to 5% by weight, about 0.005 to 3% by weight, about 0.005 to 2% by weight, about 0.01 to 10% by weight, about 0.01 to 8% by weight, about 0.01 to 5% by weight, about 0.01 to 3% by weight, about 0.01 to 2% by weight, about 0.05 to 10% by weight % by weight, about 0.05 to 8% by weight, about 0.05 to 5% by weight, about 0.05 to 3% by weight, about 0.05 to 2% by weight, about 0.1 to 10% by weight, about 0.1 to 8% by weight, about 0.1 to 5 by weight %, about 0.1 to 3% by weight, about 0.1 to 2% by weight, about 0.5 to 10% by weight, about 0.5 to 8% by weight, about 0.5 to 5% by weight, about 0.5 to 3% by weight, about 0.5 to 2% by weight , about 1 to 10% by weight, about 1 to 8 wt%, about 1 to 5 wt%, about 1 to 3 wt%, about 1 to 2 wt%.

The content of GGA in the solid preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, still more preferably 0.1 mg or more, based on the total amount of the preparation. Further, it is preferably 1000 mg or less, more preferably 100 mg or less, still more preferably 10 mg or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be 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, about 0.1 to 1000 mg, based on the total amount of the preparation. About 0.1 to 100 mg, about 0.1 to 10 mg.

pH value

When the ophthalmic agent is a preparation containing water, the pH of the ophthalmic agent is preferably 4 or more, more preferably 5.5 or more, still more preferably 6 or more, and still more preferably 6.5 or more. In addition to the above range, in addition to the preparation of GGA which is excellent in heat and light stability, the effects of the present invention are more significantly exerted.

Further, it is preferably 9 or less, more preferably 8.5 or less, still more preferably 8 or less, still more preferably 7.5 or less. As long as it is within the above range, irritation to the eyes can be suppressed.

The viscosity of the ophthalmic preparation can be appropriately set depending on the type and content of the corresponding preparation component, 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, preferably 0.01 to 10000 mPa, is measured by a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34 ‘×R24). s, more preferably 0.05 to 8000mPa. s, more preferably 0.5 to 1000 mPa. s.

Sustained release intraocular implant

Further, the ophthalmic preparation may also be a sustained release intraocular implant. A variety of methods for modulating sustained release intraocular implants are known. For example, a matrix preparation in which GGA is mixed with a carrier containing a high molecular substance, a preparation in which a core containing GGA is coated with a polymer film, and a capsule preparation in which GGA is enclosed in a microcapsule composed of a high molecular substance Wait.

As the polymer, a polymer used for the sustained release intraocular implant can be used without limitation, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose phthalate. Formate, pullulan, gelatin, collagen, atelocollagen, hyaluronic acid, casein, agar, gum arabic, dextrin, ethylcellulose, methylcellulose, chitin, Chitosan, mannan, carboxymethylethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, sodium alginate, polyvinyl alcohol, cellulose acetate, polyvinylpyrrolidone, poly Oxide, polyvinyl acetal diethylaminoacetate, albumin and lactic acid/glycolic acid copolymer.

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

The sustained release intraocular implant preferably contains GGA and other ingredients for preventing, improving or treating retinal diseases. The combination thereof can be exemplified, for example, as described above. The sustained release intraocular implant may further contain other pharmacologically active ingredients or physiologically active ingredients. As the component, for example, those exemplified above can be used. Other than the content of other components represented by GGA, it is also exemplified above. The sustained-release intraocular implanting agent is not limited to a solid, and may have a semi-solid state, a gel form, a fluid form, or a liquid form.

Sustained release contact lens preparation

Further, the ophthalmic agent can be exemplified by a sustained-release contact lens preparation containing GGA in the contact lens body. Such a sustained-release preparation can be prepared, for example, by immersing a contact lens in a contact lens liquid containing GGA, for example, a cleaning solution, a preservation solution, a disinfecting solution, a multifunctional liquid, a packaging liquid, or the like. Alternatively, the raw materials of the contact lens can be used, for example, the constituent monomers of the contact lens polymer (hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, ethylene) After the GGA is impregnated with an alcohol dimethacrylate or benzoin methyl ether, a coloring agent or an ultraviolet absorber, the contact lens is prepared by using these.

The sustained release contact lens preparation preferably contains GGA and other ingredients for preventing, ameliorating or treating retinal diseases. The combination can be exemplified, for example, as described above. The sustained release contact lens preparation may further contain a pharmacologically active ingredient or a physiologically active ingredient other than GGA. As the component, for example, those exemplified above can be used. The content of the component represented by GGA is also exemplified as described above. The sustained release contact lens preparation is not limited to a solid, and may have a semisolid state, a gel form or the like.

(2) nose spray

The agent of the present invention can be used as a nasal spray. The type, usage, and amount of the nasal spray are as follows, the properties of the composition, the nature of the composition, the types of other components that can be formulated, and the contents of the respective components are the same as those for the ophthalmic agent.

The type of the nasal spray is not particularly limited. For example, a nasal spray, a nasal spray, a nasal wash, a nasal ointment, and a nasal spray may be mentioned. From the point of good transfer to the affected part, it is preferred to use nasal spray and soft nose. Cream, better for nasal spray.

(3) internal medicine

The agent of the present invention can be used as an internal or oral administration. The internal preparation is not particularly limited, and examples thereof include a tablet (including a sublingual tablet, an orally disintegrating tablet), a capsule (including a soft capsule, a microcapsule), a granule, a powder, a tablet, and a chew. A solid preparation of a troche agent; a liquid preparation such as a syrup agent, an emulsion or a suspension, and the like.

The solid preparation may be formulated with a pharmaceutically acceptable carrier in a GGA geometric isomer mixture, and a pharmaceutically acceptable internal drug additive, and a pharmacologically active ingredient or a physiologically active ingredient other than GGA, for example, as described in the Japanese Pharmacopoeia. A known method of modulation.

The pharmaceutically acceptable carrier is not limited thereto, and examples thereof include lactose, white sugar, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, and low-substituted hydroxypropylcellulose. Excipients of sodium carboxymethylcellulose, gum arabic, polytriglucose, light phthalic anhydride, synthetic aluminum citrate, magnesium aluminometasilicate; such as alpha starch, sucrose, gelatin, gum arabic, Methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, polytriglucose, hydroxypropylcellulose, hydroxypropylmethyl Adhesives of cellulose and polyvinylpyrrolidone; such as lactose, white sugar, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light enamel An acid anhydride, a disintegrant of low-substituted hydroxypropylcellulose; such as citrate, sodium laurate, stabilizer of glycerin, and the like.

Moreover, the liquid preparation can also be recorded, for example, in the Japanese Pharmacopoeia. A known method of modulation. For example, it is prepared by dissolving or dispersing GGA in water, ethanol, glycerin, simple syrup, or a mixture thereof.

The internal preparation may be added with additives such as a sweetener, a preservative, a slip agent, a diluent, a buffer, a flavoring agent, a coloring agent, and an antioxidant for internal use.

The internal preparation preferably comprises a combination of GGA and an ingredient which is different from the agent of the present invention for preventing or treating retinal diseases. The combination is not limited thereto, and examples thereof include GGA and acetazolamide, GGA and methazolamide, GGA and diclofenamide GGA and carbonic anhydrase. Combination of inhibitors; such as GGA and concentrated glycerin, GGA and isosorbide GGA combined with high osmotic pressure drugs.

Among them, a combination of GGA and a carbonic anhydrase inhibitor is preferred, and a combination of GGA and acetonitrile azoamine and a combination of GGA and carbamide, and more preferably a combination of GGA and carbamide.

One component may be used alone or in combination of two or more kinds, which may be used for the prevention or treatment of retinal diseases.

The internal preparation may contain a pharmacologically active ingredient or a physiologically active ingredient other than the component for preventing, ameliorating or treating the retinal disease.

In particular, as a known pharmacologically active ingredient or physiologically active ingredient, for example, a neurotrophic factor, a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine component or an antiallergic drug may be mentioned. Ingredients, vitamins, amino acids, antibacterial ingredients or bactericides Ingredients, etc.

When the internal preparation is a solid preparation, the GGA content thereof is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, still more preferably 0.05% by weight based on the total amount of the composition. More than %, more preferably 0.1% by weight or more. Further, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less.

When the internal preparation is a solid preparation, the GGA content thereof may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, and about 0.005, based on the total amount of the preparation. Up to 80% by weight, about 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to about 10% by weight, about 0.05 to 80% by weight, about 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1 to 50% by weight % by weight, about 0.1 to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

Moreover, in the case of a liquid preparation, it is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, based on the total amount of the composition. More preferably, it is 0.1% by weight or more. Moreover, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less.

When the internal preparation is a liquid preparation, it may be enumerated with respect to the total amount of the preparation, wherein the content of GGA may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, and about 0.001 to 10% by weight. About 0.005 to 80% by weight, about 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight, about 0.05 to 80% by weight, about 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1% Up to 50% by weight, about 0.1 to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

In the internal preparation, the carrier, the additive, and the pharmacologically active ingredient or the physiologically active ingredient other than GGA may be used alone or in combination of two or more.

(4) Injection

The injection can be prepared by, for example, a known method described in the Japanese Pharmacopoeia by dissolving or dispersing the GGA geometric isomer mixture in distilled water for injection or physiological saline. Further, the injection may further contain a pharmaceutically acceptable carrier such as a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a pain-relieving agent, a tranquilizing agent, and a preservative, or a further pharmaceutically acceptable additive for an injection.

The injection preferably contains, in addition to GGA, It is a component that prevents or treats retinal diseases by acting differently from GGA. That is, the injection preferably contains a combination of GGA and other ingredients as an active ingredient for preventing, ameliorating or treating retinal diseases. The component which can prevent or treat a retinal disease by the action of GGA may be used alone or in combination of two or more.

The combination is not limited to the following, and examples thereof include, for example, a combination of GGA and a prostaglandin-based agent (GGA and latanoprost, GGA and travoprost, GGA and fluoroprostaglandin), GGA and Combination of GGA and prostaglandin F2 α derivatives of a combination of a prostamide-based agent (GGA and bimatoprost), a combination of GGA and a prostaglandin-based agent (GGA and isopropyl unprostone); Such as the combination of GGA and beta blockers (GGA and timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA and gelatinized carteolol, etc.) Combination of GGA and β 1 blocker (GGA with betaxolol hydrochloride, GGA and α β blockers (GGA with levobunolol hydrochloride, GGA and Nip) Dilo, etc., combination of GGA and α 1 blocker (GGA and bunazol hydrochloride And other combinations of GGA and sympathetic blockers; such as GGA and pilocarpine hydrochloride, GGA and bromide combination of GGA and parasympathetic agonist; such as GGA and epinephrine, GGA and hydrogen tartrate, GGA Combination with GGA and sympathetic agonist in combination with dipivoxil hydrochloride, GGA and α 2 agonist (GGA and brimonidine tartrate, etc.); eg GGA with acetamidine, GGA and Dozzo Combination of dozolamide hydrochloride, GGA and brinzolamide GGA with carbonic anhydrase inhibitors; eg GGA with fasudil hydrochloride, GGA and Y-27632, GGA and AR-12286, GGA and INS -117548, GGA and SNJ-1656, GGA and K-115 GGA and ROCK (Rho-related spiral curl protein kinase specific inhibitor combinations; such as GGA and Lomel Combination of GGA and calcium antagonists of hydrochloride; such as GGA and DE-117 combination of GGA and EP2 agents; such as GGA and OPA-6566 combination of GGA and adenosine A2a receptor agonist; such as GGA and Combination of VEGF aptamer (GGA and pegaptanib sodium), GGA and VEGF inhibitor combination (GGA and Lenny monoclonal antibody, GGA and Bevac monoclonal antibody) GGA and age-related macular degeneration therapeutic agent Combinations, etc.

Among them, from the point of prevention, improvement, and treatment of retinal diseases, the combination of GGA and prostaglandin F2 α derivatives, GGA and sympathetic block drugs (especially GGA and β resistance) are preferred. Combination of drug breaks), combination of GGA and ROCK inhibitors, and combination of GGA and carbonic anhydrase inhibitors.

In the case of an injection, a pharmacologically active ingredient or a physiologically active ingredient other than the component for preventing, ameliorating or treating retinal diseases can be formulated. Examples of the pharmacologically active ingredient or physiologically active ingredient include a neurotrophic factor, a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine component or an antiallergic component, a vitamin, Amino acids, antibacterial ingredients or bactericidal ingredients.

The content of GGA in the injection is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, and still more preferably the total amount of the preparation. 0.1% by weight or more. Moreover, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the injection may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, about 0.005 to 80% by weight, or about the total amount of the preparation. 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight, about 0.05. Up to 80% by weight, about 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1 to 50% by weight, about 0.1 to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

In the case of the injection, the pharmacologically active ingredient or the physiologically active ingredient other than the GGA may be used alone or in combination of two or more.

(5) Percutaneous absorption agent

The percutaneous absorption agent may, for example, be a coating agent in which a GGA geometric isomer mixture is mixed with a base (a pharmaceutically acceptable base) which is usually used for a pharmaceutical external preparation, and a component other than GGA.

The base may be exemplified by sodium alginate, gelatin, corn starch, tragacanth, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, tri-sacral gum, carrageenan, mannan, agarose , dextrin, carboxymethyl starch, polyvinyl alcohol, Sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinylpyrrolidone, carboxyvinyl polymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polytriglucose and other polymers Class; white petrolatum, yellow petrolatum, paraffin wax, ceresin wax, microcrystalline wax and other hydrocarbons; gelled hydrocarbon (for example, trade name: Plastisol squibb company); hard fat Higher fatty acids such as acid; higher alcohols such as cetyl alcohol, octyldodecanol, stearyl alcohol; polyethylene glycol (eg Macrogol 4000, etc.); propylene glycol, glycerin, dipropylene glycol, 1,3-butanediol, concentrated glycerin Such as polyols; fatty acid esters such as monooleate and glyceryl stearate. Further, a pharmaceutically acceptable percutaneous absorption additive such as a solubilizing agent, an inorganic filler, a moisturizing agent, a preservative, a thickener, an antioxidant, and a cooling agent may be added.

Further, the percutaneous absorption agent may be a patch (patch) in which a coating agent layer containing GGA and a support supporting the layer are integrated. The preparation method of the patch is known to those skilled in the art, and can be prepared, for example, by a known method described in the Japanese Pharmacopoeia.

In the case of the slab, the coating agent layer may be laminated to have a GGA concentration gradually increased to ensure the sustained release of GGA.

Further, examples of the percutaneous absorption agent include coating agents containing emulsified particles containing GGA. These can be obtained by stirring and mixing GGA together with a surfactant (phospholipid, a nonionic surfactant, etc.), water, and an oily base. Examples of the oily base include the above-exemplified hydrocarbons, higher fatty acids, higher alcohols, polyhydric alcohols, and fatty acid esters.

Further, examples of the percutaneous absorption agent include those in which a GGA suspension is dispersed as a fine particle in a hydrophobic polymer. Hydrophobic polymer It is not particularly limited, and examples thereof include polylactic acid.

The percutaneous absorption agent preferably contains, in addition to GGA, a component which inhibits or treats retinal diseases by a different action from GGA. That is, the transdermal absorbent preferably contains a combination of GGA and other ingredients as an active ingredient for preventing, ameliorating or treating retinal diseases. The component which can prevent or treat a retinal disease by the action of GGA may be used alone or in combination of two or more.

The combination is not limited to the following, and examples thereof include, for example, a combination of GGA and a prostaglandin-based agent (GGA and latanoprost, GGA and travoprost, GGA and fluoroprostaglandin), GGA and Combination of GGA and prostaglandin F2 α derivatives of a combination of a protopamine drug (GGA and bimatoprost), a combination of GGA and a prostaglandin agent (GGA and isopropyl unprostone); such as GGA and Combination of beta blockers (GGA with timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA and gelatinized carteolol, etc.), GGA and beta 1 combination of blocking drugs (GGA and betaxolol hydrochloride, etc.), combination of GGA and αβ blockers (GGA and levobronol hydrochloride, GGA and nipudallo, etc.), GGA and α 1 resistance Combination of drugs (GGA and bunazole hydrochloride) And other combinations of GGA and sympathetic blockers; such as GGA and pilocarpine hydrochloride, GGA and bromide combination of GGA and parasympathetic agonist; such as GGA and epinephrine, GGA and hydrogen tartrate, GGA Combination with GGA and sympathetic agonist in combination with dipivoxil hydrochloride, GGA and α 2 agonist (GGA and brimonidine tartrate, etc.); eg GGA with acetamidine, GGA and Dozzo Combination of amine hydrochloride, GGA and brinzolamide GGA with carbonic anhydrase inhibitor; eg GGA with fasudil hydrochloride, GGA and Y-27632, GGA and AR-12286, GGA and INS-117548, GGA Combination of GGA and ROCK (specific inhibitors of Rho-associated spiral coiled protein kinases with SNJ-1656, GGA and K-115; eg GGA and Lomeli Combination of GGA and calcium antagonists of hydrochloride; such as GGA and DE-117 combination of GGA and EP2 agents; such as GGA and OPA-6566 combination of GGA and adenosine A2a receptor agonist; such as GGA and Combination of VEGF aptamer (GGA and pegaptanib sodium), GGA and VEGF inhibitor combination (GGA and Lenny monoclonal antibody, GGA and Bevac monoclonal antibody) GGA and age-related macular degeneration therapeutic agent Combinations, etc.

Among them, from the point of prevention, improvement, and treatment of retinal diseases, the combination of GGA and prostaglandin F2 α derivatives, GGA and sympathetic block drugs (especially GGA and β resistance) are preferred. Combination of drug breaks), combination of GGA and ROCK inhibitors, and combination of GGA and carbonic anhydrase inhibitors.

The percutaneous absorption agent may be formulated to prevent, ameliorate or treat a pharmacologically active ingredient or a physiologically active ingredient other than the component of the retinal disease. The pharmacologically active ingredient or physiologically active ingredient may, for example, be a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine drug component or an antiallergic drug component, a vitamin, an amino acid, Antibacterial or bactericidal ingredients.

The content of GGA in the percutaneous absorption agent is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, and more preferably the total amount of the preparation. Preferably it is 0.1% by weight or more. Moreover, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the percutaneous absorption agent relative to the total amount of the preparation may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, and about 0.005 to 80% by weight. %, about 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight , about 0.05 to 80% by weight, about 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1 to 50% by weight, About 0.1 to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

In the percutaneous absorption agent, the pharmacologically active ingredient or the physiologically active ingredient other than the GGA may be used alone or in combination of two or more.

(6) suppository

a suppository by blending a GGA geometric isomer mixture with a propylene polymer such as Carbopol and Polycarbophil; a fibrous polymer such as hydroxypropylcellulose and hydroxypropylmethylcellulose; A pharmaceutically acceptable base such as a natural polymer of sodium alginate and chitosan; and a fatty acid wax is prepared by a known method such as the method described in the Japanese Pharmacopoeia.

Suppositories can also be formulated such as sodium benzoate, potassium sorbate and parabens. Preservatives for acid esters; pH adjusting agents such as hydrochloric acid, citric acid and sodium hydroxide; additives for pharmaceutically acceptable suppositories such as stabilizers for methionine.

Preferably, the suppository contains, in addition to GGA, a component which prevents or treats retinal diseases by a different action from GGA. That is, the suppository preferably contains a combination of GGA and other ingredients as an active ingredient for preventing, ameliorating or treating retinal diseases. The component which can prevent or treat a retinal disease by the action of GGA may be used alone or in combination of two or more.

The combination is not limited to the following, and examples thereof include, for example, a combination of GGA and a prostaglandin-based agent (GGA and latanoprost, GGA and travoprost, GGA and fluoroprostaglandin), GGA and Combination of GGA and prostaglandin F2 α derivatives of a combination of a protopamine drug (GGA and bimatoprost), a combination of GGA and a prostaglandin agent (GGA and isopropyl unprostone); such as GGA and Combination of beta blockers (GGA with timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA and gelatinized carteolol, etc.), GGA and beta 1 combination of blocking drugs (GGA and betaxolol hydrochloride, etc.), combination of GGA and αβ blockers (GGA and levobronol hydrochloride, GGA and nipudallo, etc.), GGA and α 1 resistance Combination of drugs (GGA and bunazole hydrochloride) And other combinations of GGA and sympathetic blockers; such as GGA and pilocarpine hydrochloride, GGA and bromide combination of GGA and parasympathetic agonist; such as GGA and epinephrine, GGA and hydrogen tartrate, GGA Combination of GGA and sympathetic agonist with combination of dipivoxil hydrochloride, GGA and α 2 agonist (GGA and brimonidine tartrate); eg GGA with acetamidine, GGA and Dozzo Combination of amine hydrochloride, GGA and brinzolamide GGA with carbonic anhydrase inhibitor; eg GGA with fasudil hydrochloride, GGA and Y-27632, GGA and AR-12286, GGA and INS-117548, GGA Combination of GGA and ROCK (specific inhibitors of Rho-associated spiral coiled protein kinases with SNJ-1656, GGA and K-115; eg GGA and Lomeli Combination of GGA and calcium antagonists of hydrochloride; such as GGA and DE-117 combination of GGA and EP2 agents; such as GGA and OPA-6566 combination of GGA and adenosine A2a receptor agonist; such as GGA and Combination of VEGF aptamer (GGA and pegaptanib sodium), GGA and VEGF inhibitor combination (GGA and Lenny monoclonal antibody, GGA and Bevac monoclonal antibody) GGA and age-related macular degeneration therapeutic agent Combinations, etc.

Among them, from the point of prevention, improvement, and treatment of retinal diseases, the combination of GGA and prostaglandin F2 α derivatives, GGA and sympathetic block drugs (especially GGA and β resistance) are preferred. Combination of drug breaks), combination of GGA and ROCK inhibitors, and combination of GGA and carbonic anhydrase inhibitors.

The suppository can be formulated with a pharmacologically active ingredient or a physiologically active ingredient other than the component for preventing, ameliorating or treating retinal diseases. Examples of the pharmacologically active ingredient or physiologically active ingredient include a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine component or an antiallergic component, a vitamin, an amino acid, Antibacterial or bactericidal ingredients.

The content of GGA in the suppository is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and more preferably, relative to the total amount of the preparation. It is 0.01% by weight or more, more preferably 0.05% by weight or more, still more preferably 0.1% by weight or more. Moreover, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the suppository may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, and about 0.005 to 80% by weight, based on the total amount of the preparation. About 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight, about 0.05 to 80% by weight, about 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1 to 50% by weight, about 0.1% Up to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

In the suppository, the additive or the pharmacologically active ingredient or the physiologically active ingredient other than GGA may be used alone or in combination of two or more.

(7) Inhalation

Examples of the inhalant include a powdered inhalant, a liquid inhalant, and an aerosol. These modulation methods are well known.

The powdery inhaler can be prepared, for example, by finely pulverizing the GGA geometric isomer mixture in a usual manner and mixing an excipient such as lactose as needed. A powdered inhaler can be administered using an inhalation device such as Spinhaler (registered trade name) Give.

The liquid inhalation solution can be prepared by adding GGA and, if necessary, a pharmaceutically acceptable liquid inhalant additive as needed, in a pharmaceutically acceptable carrier such as purified water or distilled water for injection, stirring and dissolving. Examples of pharmaceutically acceptable additives for liquid inhalants include, for example, a sizing agent such as sodium chloride, such as a buffer of boric acid buffer and a phosphate buffer, such as a preservative of benzalkonium chloride, such as a carboxyvinyl polymer. Adhesives, etc. The liquid inhalant can be administered using an inhalation device such as Nebulizer (registered trade name).

The aerosol can be prepared, for example, by finely pulverizing GGA in a usual manner, adding a dispersing agent as needed, and filling it in a spray container together with a propellant under cooling. The propellant may, for example, be a liquefied hydrofluoroalkane (HFA 134a (1,1,1,2-tetrafluoroethane; CH ₂ FCF ₃ ), HFA 227 (1,1,1,2,3,3,3-heptafluoropropane: CF ₃ -CHF-CF ₃ ), etc.). Examples of the dispersant include, for example, Miglyol 812 (trademark: manufactured by Dynamit Nobel Co., Ltd.) medium chain fatty acid triglyceride, soybean lecithin, and the like.

Preferably, the inhalant contains, in addition to GGA, a component which prevents or treats retinal diseases by a different action from GGA. That is, the inhalant preferably contains a combination of GGA and other components as an active ingredient for prevention, amelioration or treatment of retinal diseases. The components which prevent or treat retinal diseases by a different action from GGA may be used alone or in combination of two or more.

The combination is not limited to the following, and examples thereof include, for example, a combination of GGA and a prostaglandin-based agent (GGA and latanoprost, GGA and travoprost, GGA and fluoroprostaglandin), GGA and Combination of GGA and prostaglandin F2 α derivatives of a combination of a protopamine drug (GGA and bimatoprost), a combination of GGA and a prostaglandin agent (GGA and isopropyl unprostone); such as GGA and Combination of beta blockers (GGA with timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA and gelatinized carteolol, etc.), GGA and beta 1 combination of blocking drugs (GGA and betaxolol hydrochloride, etc.), combination of GGA and αβ blockers (GGA and levobronol hydrochloride, GGA and nipudallo, etc.), GGA and α 1 resistance Combination of drugs (GGA and bunazole hydrochloride) And other combinations of GGA and sympathetic blockers; such as GGA and pilocarpine hydrochloride, GGA and bromide combination of GGA and parasympathetic agonist; such as GGA and epinephrine, GGA and hydrogen tartrate, GGA Combination with GGA and sympathetic agonist in combination with dipivoxil hydrochloride, GGA and α 2 agonist (GGA and brimonidine tartrate, etc.); eg GGA with acetamidine, GGA and Dozzo Combination of amine hydrochloride, GGA and brinzolamide GGA with carbonic anhydrase inhibitor; eg GGA with fasudil hydrochloride, GGA and Y-27632, GGA and AR-12286, GGA and INS-117548, GGA Combination of GGA and ROCK (specific inhibitors of Rho-associated spiral coiled protein kinases with SNJ-1656, GGA and K-115; eg GGA and Lomeli Combination of GGA and calcium antagonists of hydrochloride; such as GGA and DE-117 combination of GGA and EP2 agents; such as GGA and OPA-6566 combination of GGA and adenosine A2a receptor agonist; such as GGA and Combination of VEGF aptamer (GGA and pegaptanib sodium), GGA and VEGF inhibitor combination (GGA and Lenny monoclonal antibody, GGA and Bevac monoclonal antibody) GGA and age-related macular degeneration therapeutic agent Combinations, etc.

Among them, from the point of prevention, improvement, and treatment of retinal diseases, the combination of GGA and prostaglandin F2 α derivatives, GGA and sympathetic block drugs (especially GGA and β resistance) are preferred. Combination of drug breaks), combination of GGA and ROCK inhibitors, and combination of GGA and carbonic anhydrase inhibitors.

The inhalant may be formulated to prevent, ameliorate or treat a pharmacologically active ingredient or a physiologically active ingredient other than the component of the retinal disease. Examples of such a pharmacologically active ingredient or a physiologically active ingredient include a decongestant component, an eye muscle regulating drug component, an anti-inflammatory drug component or an astringent drug component, an antihistamine component or an antiallergic component, a vitamin, an amino acid, Antibacterial or bactericidal ingredients.

The content of GGA in the inhalant is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, even more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, still more preferably 0.1% by weight based on the total amount of the preparation. %the above. Further, it may be 1% by weight or more. Further, it is preferably 80% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less. Further, it may be 10% by weight or less. As long as it is in the above range, sufficient effects of preventing, improving or treating retinal diseases can be obtained.

The content of GGA in the inhalant may be, for example, about 0.001 to 80% by weight, about 0.001 to 60% by weight, about 0.001 to 50% by weight, about 0.001 to 10% by weight, and about 0.005 to 80% by weight, based on the total amount of the preparation. About 0.005 to 60% by weight, about 0.005 to 50% by weight, about 0.005 to 10% by weight, about 0.01 to 80% by weight, about 0.01 to 60% by weight, about 0.01 to 50% by weight, about 0.01 to 10% by weight, about 0.05 to 80% by weight, About 0.05 to 60% by weight, about 0.05 to 50% by weight, about 0.05 to 10% by weight, about 0.1 to 80% by weight, about 0.1 to 60% by weight, about 0.1 to 50% by weight, about 0.1 to 10% by weight, about 1 to 80% by weight, about 1 to 60% by weight, about 1 to 50% by weight, and about 1 to 10% by weight.

In the inhalation, the additive and the pharmacologically active ingredient or the physiologically active ingredient other than the GGA may be used alone or in combination of two or more.

Kit

The agent of the present invention may be composed of one dosage form composition containing all the components, or may be any type of set such as two dosage forms or three dosage forms. The kit includes a kit containing a composition of GGA and a composition containing a pharmacologically active component or a physiologically active component other than GGA, each having a composition containing a specific additive, a composition containing GGA, and the like. In the case of a kit, the components may be filled in different containers, or may be a ready-to-use composition that is filled in a container that can be mixed at the time of use.

When the agent body of the present invention is a set containing a composition of a GGA and a composition containing other components, whether the composition is filled in a set of different containers or a set of a modulation type at the time of use, The GGA content of each of the formulations described is a ratio relative to the total amount after mixing the respective compositions.

Subject disease

The retinal disease of the present invention may be a disease caused by a lesion, a disorder or a cell necrosis of a cell constituting the retina, or a disease caused by a cell lesion, a disorder or a cell necrosis of the retina, for example, Glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular degeneration, hypertensive retinopathy, retinal vascular occlusion (retinal artery occlusion; such as central retinal vein occlusion, retinal central venous branch obstruction) Retinal vein occlusion, etc., retinal arteriosclerosis, retinal tears, retinal holes, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented venous retinal choroidal atrophy, cerebral gyrus retinal choroidal atrophy, choroid-free, crystalline Retinopathy, white spot retinopathy, cone dystrophy, central halo-like choroidal dystrophy, Dorn's honeycomb retinal dystrophy, yolk-like macular dystrophy, cystic macular edema, cryptic macular dystrophy, Stargardt disease, retinal sepsis, central serous retinal choroidosis (central retinopathy), spinal cord cerebral dysfunction type 7, familial exudative vitreoretinopathy, short-wave sensitive cone Enhance syndrome, Retinal vascular disease streaks, autosomal dominant optic atrophy, dominant drusen, familial drusen, acute strip cryptogenic outer retinopathy, cancer-related retinopathy, ischemic retinal light damage and psychosis.

Among them, glaucoma, retinopathy, age-related macular degeneration, and diabetic retinopathy are suitable diseases, and glaucoma is a more suitable disease.

Furthermore, the present invention can also be made into a disease in which any of the cells of the retina is subjected to a disorder, or a disease caused by any of the cell disorders constituting the retina. Examples of the retinal constituting cells include retinal ganglion cells, amacrine cells, horizontal cells, muller glial cells, bipolar cells, and retinal cells. (cone cells, rod cells) and retinal pigment epithelial cells. In particular, it is suitable for identifying a disorder of retinal ganglion cells or retinal pigment epithelial cells or a disease caused by such cellular disorders.

Moreover, the present invention constitutes a layer of the retina, that is, an inner limiting membrane, a nerve fiber layer, a ganglion cell layer, an inner reticular layer, an inner granular layer, an outer reticular layer, an outer granular layer, an outer limiting membrane, and a visual cell. Any of the layers and the retinal pigment epithelial layer are affected by the disease, or the disease caused by any of these layers of disorders. In particular, diseases of the ganglion cell layer, the inner granular layer or the outer granular layer are suitable targets.

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

A suitable patient for the subject of the present invention is a patient of the above retinal disease.

As described above, the agent system of the present invention promotes retinal cell survival by using GGA geometric isomer mixture containing only a specific GGA geometric isomer or containing a specific GGA geometric isomer ratio of 80% by weight or more as GGA. , inhibit retinal cell lesions, disorders or apoptosis, and protect retinal cells. Moreover, by inducing and even promoting the elongation of neurites of cells, especially retinal cells, the function of cells is improved, and the survival state of cells is improved and even improved. In addition, inflammation of the retina is inhibited by inhibiting inflammatory cytokines produced from retinal cells. By such effects, the agent system of the present invention prevents, ameliorates or treats retinal diseases.

Accordingly, the present invention includes: a retinoic cell protective agent comprising only a specific GGA geometric isomer or a GGA geometric isomer mixture having a specific GGA geometric isomer ratio of 80% by weight or more as an active ingredient, retinal cytopathic, Inhibitor of dysfunction or apoptosis, neurite elongation inducer (especially retinal neurite elongation inducer), cell function enhancer (especially retinal cell function enhancer), improvement of cell survival status or enhancer (especially improvement or enhancer of retinal cell survival status) and retina and even retina An inhibitor of inflammation of cells.

Among such agents, suitable retinal cell types are as described above. The ingredients in the preparation, the amount thereof to be used, the properties of the preparation, the dosage form, and the like are as described in the prevention, amelioration or therapeutic agent for retinal diseases of the present invention.

In the present invention, "prevention" includes avoiding, delaying the onset of the disease or reducing the incidence. "Improvement" and "treatment" include symptom relief, inhibition of symptoms, healing and even healing.

Instructions <Ophthalmic preparation>

When the dosage form of the present invention is an eye drop, the eye drops containing GGA of the above concentration are, for example, about 1 to 5 drops, preferably about 1 to 3 drops, more preferably about 1 to 2 drops, per hour. The eye is about 1 to 7 times on the 1st, preferably about 1 to 5 times, more preferably about 1 to 3 times.

When the agent of the present invention is an eye-washing agent, the eye-washing agent containing the GGA of the above concentration is used, for example, about 1 to 20 mL per one time, and the eye is washed about 1 to 10 times a day, preferably about 1 to 5 times. .

Further, when the agent of the present invention is an ophthalmic ointment, the ophthalmic ointment containing the GGA of the above concentration is applied to the eye about 1 to 7 times, for example, about 1 to 7 times, preferably about 1 to 7 g per day. Up to 5 times, more preferably about 1 to 3 times.

Moreover, when the agent of the present invention is an intraocular injection, it will contain the above-mentioned concentrated The injection of GGA is injected in an amount of about 0.005 to 1 mL per injection, and is injected about 1 to 3 times from 1 to 14 days, preferably once.

Further, the agent of the present invention is a solution for a contact lens (a cleaning solution, a preservation solution, a disinfectant, a multifunctional liquid, a packaging liquid), a preservation agent for an eye tissue extracted by a cornea for transplantation, or a perfusate for surgery. The composition containing the GGA of the above concentration may be used in the usual amounts of the preparations.

Moreover, when the dosage form of the present invention is a sustained-release contact lens preparation, the contact lens containing the above-mentioned amount of GGA is replaced with a new product by about 1 to 3 times, for example, from 1 to 14 days, preferably for replacement into a new product. Just fine.

Further, when the agent of the present invention is a sustained-release intraocular implant, there is a case where a new implant cannot be replaced, and a new implant containing the above-mentioned amount of GGA may be replaced. For example, it can be replaced once in about 1 to 10 years. For example, if the replacement period of the implant in the posterior eye is longer, there is also a new implant that is replaced once between about 1 and 14 days.

Regardless of the dosage form of the ophthalmic composition, the GGA has a daily dose of preferably 50 ng or more, more preferably 500 ng or more, still more preferably 5 μg or more. Further, the amount of GGA administered on the 1st day is preferably 50 mg or less, more preferably 20 mg or less, still more preferably 10 mg or less.

The ophthalmic agent of any one of the dosage forms, the one-day administration amount of GGA may 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, about 5 μg to 20 mg, about 5 μg to 10 mg.

<Nasal>

When the agent of the present invention is a nasal spray, it is the same as the ophthalmic agent. The concentration of the nasal preparation containing GGA is, for example, about 0.0005 to 5 mL each time, about 1 to 5 times per day, preferably about 1 to 3 times, and the nose can be sprayed or the like.

<Other preparations>

When the dosage form of the present invention is a dosage form other than an ophthalmic preparation or a nasal spray, the daily dose of GGA is preferably about 0.1 mg or more, more preferably about 1 mg or more, still more preferably about 5 mg or more. Further, it is preferably about 5,000 mg or less, more preferably about 1,000 mg or less, still more preferably about 500 mg or less.

When the dosage form of the present invention is a dosage form other than an ophthalmic preparation, the one-day administration amount of GGA may preferably be about 0.1 to 5000 mg, more preferably about 1 to 1000 mg, still more preferably about 5 to 500 mg. The above-mentioned 1-day administration amount can be divided into, for example, about 1 to 5 times a day, preferably about 1 to 3 administrations.

The period of administration varies depending on the type, degree, age, weight, sex, route of administration, and the like of the disease, and can be appropriately selected, for example, in the range of about 1 to 30 years. For example, in the case of retinal diseases such as glaucoma, retinopathy, age-related macular degeneration, and diabetic retinopathy, there may be prevention, improvement, or prevention during a so-called short-term administration period of about 1 to 20 years, especially about 1 to 10 years. Treatment of retinal diseases. When the ophthalmic composition of the present invention inhibits retinal diseases by retinal protection, continuous administration is also possible.

The present invention is a method for administering a GGA geometric isomer mixture having an effective amount of a specific GGA geometric isomer or a specific GGA geometric isomer ratio of 80% by weight or more to a retinal disease patient for preventing, improving or treating the retina The method of disease, the way to protect retinal cells Methods, methods for inhibiting retinal cytopathy, disorders or apoptosis, methods for inducing neurite elongation (especially methods for inducing retinal neurite elongation), methods for improving cellular function (especially methods for improving retinal cell function), and enhancing cell survival State methods and methods of inhibiting inflammation of the retina.

The GGA may be administered in the form of each of the preparations of the present invention described above. The method of administration varies depending on the dosage form, and may be enumerated: eye, eye wash, application to the eye, spray to the eye, implantation into the eye, use of contact lenses, injection (injection into the vitreous, etc., intravenous injection) , subcutaneous injection, intramuscular injection), spray to the nose, internal, percutaneous, inserted into the rectum, inhalation, etc. When it is used as an ophthalmic agent, it can be administered to the eye.

The subject disease, the subject patient, and the type of retinal cells are as described in the paragraphs illustrating the agent of the present invention.

[Examples]

Hereinafter, the present invention will be described in detail by way of examples, but the invention is not limited to the examples. Further, in the following examples, the content of the component is expressed by w/v%, and the component content expressed by w/v% and the component content expressed by weight% are considered in consideration of the composition of the respective samples. Is essentially the same value.

(1) Preparation of geranylgeranylacetone

Purchasing commercially available teprenone (all-trans form: 5Z single-cis form = weight ratio 3:2) (manufactured by Wako Pure Chemical Industries, Ltd.), refining all-trans and 5Z-single bodies by gel chromatography .

The specific conditions were that silicone rubber (PSQ60B, manufactured by Fuji Silysia Chemical) was filled in a glass tube by a mobile phase (n-hexane: ethyl acetate = 9: 1) Separate and refine. After the fractionation, the fractions were concentrated and dried under reduced pressure, and the whole trans-body system was confirmed by GC and 1H-NMR (solvent: heavy chloroform, internal standard: tetramethyl decane). And structure. The yield of all trans is about 20%.

<GC measurement conditions>

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

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

Gasification chamber temperature: 280 ° C

Detector temperature: 280 ° C

Carrier gas: 氦

Hydrogen pressure: 60kPa

Air pressure: 50kPa

Additional air pressure: 75kPa (nitrogen gas)

Total flow: 41mL/min

Column flow: 6.52mL/min

Linear speed: 58.3cm / sec

Split ratio: 5:1

Injection amount: 1 μL of sample injected into 0.1 g/100 mL (ethanol solution)

The commercially available teprenone is mixed with the all-trans form purified by the above operation at any ratio to prepare each weight ratio (all-trans form: 5Z single-cis form = weight ratio 1:9, 2: 8, 7:3, 8:2, 9:1) GGA. These are modulated at the time of use.

(2) Evaluation of the effect of protecting hypoxic/low glucose-induced ischemic cell necrosis on retinal neurons

The progression of visual impairment in glaucoma is associated with poor blood flow near the optic nerve leading to necrosis of the optic ganglion cells (RGC) (Folia pharmacol. Jpn. 128, 255 to 258 (2006)). It is used as a representative neural cell strain established from rat para-kidney pheochromocytoma, and also as a model cell evaluated by RGC function (J Neurosci Res. 2000 May 15; 60(4): 495-503.) PC12, the effect of GGA on protecting cells from hypoxia and low glucose-induced ischemia-like cell necrosis.

evaluation method

The test substance was prepared by the operation as described below. That is, the test substance is four kinds of GGAs which are contained in the weight ratio of 10:0, 8:2, 6:4, and 0:10 in the total trans form and the 5Z single cis form. Each GGA 100 mg and DL-α-tocopherol (manufactured by Wako Pure Chemical Industries, Ltd.) as an antioxidant were weighed in an amount of 0.25 mg, and dissolved in 100% ethanol (789 mg), and the same operation was carried out except for the absence of GGA. 789mg of 10:0, 8:2 and 6:4 GGA will be dissolved in 100% ethanol, with 10% (v/v) horse serum (DS Pharma Biomedical), 5% (v/v) fetal calf In the high-glucose concentration (4.5 g/L) of the serum (the first chemical company), the Dubeck modified Eagle basal medium (DMEM) was diluted to a concentration of 30 μM in total, and only the total concentration was 30 μM. The 5Z single-cis type 0:10 GGA was diluted to 30 μM. The base was diluted at the same dilution ratio as the GGA in which the weight ratio of the all-trans form to the 5Z single-cis form was 6:4.

PC12 (available from DS Pharma Biomedical Co., Ltd.) was inoculated with 100 μL of each of the cells in a 96-well microplate (IWAKI) coated with collagen IV to make 2.0×10 ⁴ cells per well, in the above DMEM at 37 ° C, 5 The conditions of %CO ₂ were cultured for 48 hours.

After culturing for 48 hours, the cell culture supernatant was removed, replaced with a previously prepared GGA-containing DMEM, and cultured at 37 ° C under 5% CO ₂ for 2 hours. After 2 hours of culture, DMEM was added to a low glucose concentration (1.0 g/L) supplemented with 2% horse serum and 1% fetal bovine serum at 37 ° C, 5% CO ₂ , using an anaerobic culture tank (AnaeroPack) 5 % (manufactured by Mitsubishi Gas Chemical Co., Ltd.) was changed to 0% O ₂ as a hypoxic condition, and cultured for 8 hours. For the addition of 2% (v / v) horse serum, 1% (v / v) fetal bovine serum high glucose concentration (4.5g / L) in DMEM, 37 ° C, 5% CO ₂ , the usual oxygen concentration The culture was carried out for 8 hours as an untreated group.

result

After culturing for 8 hours, 100 μL of each cell was mixed with a live cell assay reagent Cell Titer-Glo (Promega) and PBS, and the reaction with ATP in living cells was measured by a luminometer (GloMax; manufactured by Promega). And the amount of luminescence generated. The effect of protecting cells by the oxidative pressure derived from hydrogen peroxide by GGA is calculated and evaluated based on the actually measured luminescence amount by the following formula.

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

The results are shown in Figure 1. As shown in the first figure, the GGA treatment group has a significantly higher cell survival rate than the base treatment group in any weight ratio. In addition, GGA with a weight ratio of all-trans and 5Z-mono-forms of 10:0, 8:2, and 0:10 has a cell protection effect of GGA significantly higher than 6:4 (n=10). , * P < 0.05, * * P < 0.01, by Tukey-kramer check. Also, no significant difference was seen between 8:2, 10:0 and 0:10).

(3) Evaluation of the effect of inducing neurite elongation using a culture line derived from rat retinal ganglion cells (RGC) (Evaluation 1)

The progression of visual impairment in glaucoma is associated with necrosis of the optic ganglion cells (RGC) due to poor blood flow near the optic nerve (Folia Pharmacol. Jpn. 128, 255-258 (2006)). Here, the effect of GGA-induced neurite elongation is tested using a rat-derived retinal nerve culture system (Current protocols in Neuroscience 3.22.1-3.22.10, October 2010) which is widely used as one of tools for studying glaucoma and the like. .

evaluation method

Four-day-old Wistar rats (Japan SLC Co., Ltd.) were euthanized by cervical dislocation and the eyeballs were removed. The extracted eyeballs were immersed in 70% ethanol for 10 seconds and then transferred to a Hank's balanced salt solution containing 100 U/mL penicillin and 100 μg/mL streptomycin under a stereoscopic microscope. The cornea, iris, crystal and vitreous were removed using surgical scissors and forceps, and the retinal tissue was removed. The extracted retinal tissue was transferred to a penicillin 100 U/mL, streptomycin 100 μg/mL, a nerve cell culture supplement (B27 ^TM -Supplement, manufactured by Invitrogen), and 1 μM L-cysteine (co-fermentation fermentation) In a 5 mL centrifuge tube of a basal medium for nerve cell culture (manufactured by Neurobasal, manufactured by Invitrogen) of papain (Sigma-Aldrich), the cells were incubated at 37 ° C for 30 minutes. After 30 minutes, the supernatant was removed, and washed twice with penicillin 100 U/mL, streptomycin 100 μg/mL, and Neurosal containing B27 ^TM -Supplement. After washing, 2 mL of Neurobasal was added, and a dry heat-sterilized Pasteur Pipette (Hilgenberg) was used to aspirate the tissue into small cell masses and transferred to a previously prepared 50 mL Neurobasal. The supernatant was removed by centrifugation at 900 × g for 5 minutes, and then resuspended in 6 mL of Neurobasal to prepare a cell suspension. The cell suspension was passed through a 40 μm nylon mesh cell strainer (BD, Japan), and the agglutinated cell mass was removed, and then the cells were seeded with poly-D-lysine/laminin (Poly-D-Lysine/Laminin). A 6-well plate (Japan BD) was incubated at 37 ° C under 5% CO ₂ .

The test substance contained two kinds of GGAs: all-trans and all-trans and 5Z-mono-form in a weight ratio of 6:4. GGA 100 mg, 0.25 mg of acetic acid DL-α-tocopherol (manufactured by Wako Pure Chemical Industries, Ltd.) as an antioxidant, and 789 mg of 100% ethanol were weighed and used as a base for the same operation except for the absence of GGA. Agent. The GGA system dissolved in 100% ethanol 789 mg at 10:0 and 6:4 was adjusted to have a concentration of 3 μM in total, and the base was diluted at the same dilution ratio as the GGA prepared at 6:4. After 2 hours of cell seeding, the cells were added to the cell culture supernatant, and cultured at 37 ° C under 5% CO ₂ for 48 hours.

result

After the culture for 48 hours, the cell culture supernatant was removed, and the cells were fixed at room temperature for 30 minutes using 4% polyoxymethylene/phosphate buffer (Wako Pure Chemical Industries, Ltd.) and 100% methanol (Wako Pure Chemical Industries, Ltd.). With phosphate buffer (PBS, KOHJIN Bio Inc.) Washed cells in PBS containing 2% (w/v) bovine serum albumin (Sigma-Aldrich), 0.05% (v/v) Tween 20 (Sigma-Aldrich) at room temperature Blocking for 30 minutes. After 30 minutes, a 1000-fold dilution of β III-tubulin antibody (Promega) was prepared in PBS, and 1 mL was added to each well, followed by incubation at room temperature for 2 hours. After 2 hours, the antibody dilution was removed, washed three times with PBS, and then diluted 1000-fold with PBS-modulated Alexa Fluor 488 Goat Anti-mouse antibody (Invitrogen), and 1 mL was added to each well, followed by incubation at room temperature for 1 hour. . After 1 hour, the antibody dilution was removed, and after washing three times with PBS, 3 mL of PBS was added to each well, and observed by imaging cytometry (In Cell Analyzer 1000, manufactured by GE Healthcare Bio-Sciences). Any 4 points of each hole (excitation wavelength 475 nm, fluorescence wavelength 535 nm). The average value of the fluorescently stained RGC neurite length (μm) was calculated.

The results are shown in Figure 2. As shown in Fig. 2, the GGA treatment group with a weight ratio of all-trans and 5Z single-cis is 10:0, and the GGA treatment group with a weight ratio of all-trans and 5Z-single is 6:4. And the base treatment group had a more pronounced neurite induction effect (n=4, *P<0.05, **P<0.01, via Tukey-kramer assay).

Further, Fig. 3 shows a representative observation image of the fluorescently stained rat RGC. It is clear that the 10:0 GGA treatment group has a significant neurite induction effect compared to the 6:4 GGA treatment group.

(4) Evaluation of the effect of induction of neurite elongation using a culture line derived from rat retinal ganglion cells (RGC) (Evaluation 2) evaluation method

Perform the same operation as "(3) Evaluation of the effect of inducing neurite elongation by a culture line derived from rat retinal ganglion cells (RGC) (Evaluation 1)", except that the test substance is a 5Z single cis, And 2 GGAs containing a mixture of all-trans and 5Z-mono-forms in a weight ratio of 2:8. Weigh 100 mg of each GGA, 0.25 mg of acetic acid DL-α-tocopherol (manufactured by Wako Pure Chemical Industries, Ltd.) as an antioxidant, and dissolve it in 789 mg of 100% ethanol, and use the same procedure as the base except for the absence of GGA. . 5Z monocis form dissolved in 789mg of 100% ethanol: GGA (5Z single cis form) with a weight ratio of all trans is 0:10, GGA mixture of 2:8 is corrected to become 5Z single cis. The medium was added at a concentration of 3 μM, and the base was added to the cell culture supernatant 2 hours after cell seeding in the same manner as in the preparation of 6:4 GGA, and cultured at 37 ° C under 5% CO ₂ . hour.

result

The fluorescence-stained RGC neurite length (μm) was calculated in the same manner as in (3) Evaluation of the effect of induction of neurite elongation by the culture line derived from rat retinal ganglion cells (RGC) (Evaluation 1). The average value is shown in Fig. 4.

As can be seen from Fig. 4, the weight ratio of the all-trans body to the 5Z-single body is 0:10 and 2:8, and the weight ratio of the all-trans body to the 5Z-single body is 6 The GGA treatment group and the base treatment group of 4 had more significant neurite induction effects (n=4, *P<0.05, **P<0.01, confirmed by Tukey-kramer).

(5) Evaluation of the effect of protecting oxidative stress from retinal pigment epithelial cells derived from hydrogen peroxide

The relationship between oxidative stress and ophthalmic diseases has been widely reported. In addition to glaucoma and cataract, in terms of retina, it is related to retinal diseases caused by diabetes, hypertension, hyperlipidemia, age-related macular degeneration, premature infants. Retinopathy, retinal vascular occlusion, retinal dysfunction, etc. (Japanese Eye Journal 112, 22-29 (2008)). In the retina, the retinal pigment epithelium is an environment prone to reactive oxygen species (Invest Opthalmol Vis Sci. 2006 July 47(7): 3164-3177.). The effect of protecting GGA from oxidative stress derived from hydrogen peroxide was tested using human-derived retinal pigment epithelial cell line ARPE-19.

evaluation method

Three kinds of GGAs containing a total trans form and a 5Z single cis form at a weight ratio of 10:0, 8:2, and 6:4 were prepared as test substances in the following manner. That is, weigh 100 mg of each GGA, 0.25 mg of acetic acid DL-α-tocopherol (Wako Pure Chemical Industries) as an antioxidant, and dissolve it in 789 mg of 100% ethanol, and use the same operation as the base except for the absence of GGA. Agent. GGA dissolved in 100% ethanol 789 mg at 10:0, 8:2 and 6:4, added to 10% (v/v) fetal bovine serum (first chemical) in Dubeck modified Eagle basal medium/ Ham's F-12 was diluted in a mixed liquid medium (DMEM/F-12, manufactured by Invitrogen) to a concentration which substantially corrected the total trans-body 280 μM. The base was diluted at the same dilution ratio as when the 6:4 GGA was prepared. The above dilution was used as the test solution.

ARPE-19 (purchased from ATCC) was seeded in a 96-well microplate (CORNING) to inoculate 100 μL of cells in a manner of 1.5×10 ⁴ cells per well, at 37 ° C, 5% CO in the above DMEM/F-12. The conditions of ₂ were cultured for 48 hours.

After 48 hours of culture, the cell culture supernatant was removed, replaced with the previously prepared test liquid, and cultured at 37 ° C under 5% CO ₂ for 14 hours. Before the completion of the culture, the precision analysis was carried out by adding hydrogen peroxide (Wako Pure Chemical Industries, Ltd.) to DMEM/F-12 to prepare DMEM/F-12 to which 750 μM hydrogen peroxide was added. After the culture for 14 hours, the cell culture supernatant was removed, and 200 μL of phosphate buffer (PBS, manufactured by Xingren Biological Co., Ltd.) was added thereto. Immediately, the PBS was removed, and the previously prepared hydrogen peroxide-added DMEM/F-12 was replaced with a condition of 37 ° C and 5% CO ₂ for 2 hours. The DMEM/F-12 which was replaced with no hydrogen peroxide was used as an untreated group.

result

After culturing for 2 hours, the cell culture supernatant was removed, and 200 μL of PBS was added thereto, followed by removal of PBS. 100 μL of the cells were mixed with a cell viability assay, Cell Titer-Glo (Promega) and PBS, and the amount of luminescence generated by reaction with ATP in living cells was measured with a luminometer (GloMax; manufactured by Promega). The effect of GGA on protecting cells from the oxidative pressure derived from hydrogen peroxide was evaluated based on the measured luminescence amount and the cell survival rate was calculated by the following formula.

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

The results are shown in Figure 5. As shown in Figure 5, in the GGA treatment group, any cell with a higher weight ratio than the base treatment group Stock rate. In addition, any of the 10:0 and 8:2 GGAs showed significantly higher cell viability than the base treatment group (n=3, *P<0.05, ***P<0.001, via Tukey-kramer assay). ).

(6) Evaluation of inhibition of IL-8 production from retinal pigment epithelial cells

Known in age-related macular degeneration, there is a hidden accumulation in the subretinal pigment epithelium, which is close to macrophages. Macrophages secrete TNF-α, and if TNF-α acts on the retinal pigment epithelium or surrounding tissues, the cells further produce various cytokines to cause inflammation (Mol Vis. 2008 14:2292-303.). Interleukin-8 (IL-8) is a representative cytokine that is involved in neutrophil migration and expands inflammation. Using the human retinal pigment epithelial cell line ARPE-19, the test GGA inhibited the production of IL-8 by TNF-α.

evaluation method

The following procedure was carried out to prepare an all-trans form and two GGAs containing a total trans form and a 5Z single cis form at a weight ratio of 6:4 as a test substance. That is, 100 mg of GGA, 0.25 mg of acetic acid DL-α-tocopherol as an antioxidant, and 789 mg of 100% ethanol were separately weighed, and the same operation was carried out as a base except for the absence of GGA. All-trans which is dissolved in 100% ethanol (789 mg) and GGA containing all-trans and 5Z-mono-forms in a weight ratio of 6:4, diluted in DMEM/F-12 to substantially contain 50 μM of all-trans The concentration was corrected by the method, and the base was diluted at the same dilution ratio as that of the GGA in which the weight ratio of the all-trans form to the 5Z single-cis form was 6:4. The above dilution system was used as the test liquid.

ARPE-19 was inoculated with 100 μL of cells in a 96-well microplate (CORNING) to make 2.5×10 ⁴ cells per well, in DMEM/F-12 supplemented with 10% (v/v) fetal bovine serum. The cells were cultured for 24 hours under the conditions of ° C and 5% CO ₂ .

After the culture for 24 hours, the cell culture supernatant was removed, and 200 μL of the previously prepared test solution was added to each well, and cultured at 37 ° C under 5% CO ₂ for 16 hours. DMEM/F-12 was also added to the untreated group and cultured. Before the completion of the culture, DMEM/F-12 was prepared in such a manner that the Human Human TNF-α (R&D Systems) became 10 ng/mL. After culturing for 16 hours, 2 μL of the previously prepared TNF-α-containing DMEM/F-12 was separately added to the test solution of each well, and cultured at 37 ° C under 5% CO ₂ for 4 hours. The untreated group was not added with TNF-α, and the same culture was carried out.

result

After culturing for 4 hours, 150 μL of the cell culture supernatant was separately collected and stored at -80 °C. The remaining cell culture supernatant was removed, and 200 μL of PBS was added thereto, followed by removal of PBS. Each cell was added with 100 μL of the same amount of live cell detection reagent Cell Titer-Glo and PBS, and the amount of luminescence generated by reaction with ATP in living cells was measured with a luminometer. Based on the measured amount of luminescence, the cell survival rate was calculated by the following formula.

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

The cell culture supernatant was returned to room temperature, and the IL-8 concentration was quantified using a Human CXCL8/IL-8 Quantikine ELISA Kit (R&D Systems). The operation is performed according to the instructions in the kit, and the measured absorbance is corrected by dividing the cell survival rate. Determination of absorbance A microplate analyzer (VersaMax, manufactured by Molecular Devices Co., Ltd., which has a length of 450 nm and a correction wavelength of 540 nm) (temperature in the apparatus is 20 to 25 ° C). The IL-8 concentration corresponding to the corrected measurement value was calculated, and the value of the IL-8 concentration of the untreated group as the background was subtracted as the IL-8 concentration of each treatment group.

The results are shown in Figure 6. From Figure 6, it is clear that the GGA (all-trans-body) treatment group with a weight ratio of all-trans and 5Z single-cis is 10:0. The weight ratio of the all-trans body to the 5Z single-cis body is The 6:4 GGA treatment group significantly inhibited IL-8 production (n=3, *P<0.05, via Tukey-kramer assay).

(7) Evaluation of the effect of neurological disorders induced by NMDA on the protection of retinal ganglion cells

In recent years, there have been many reports of NMDA (N-methyl-D-aspartate), which is a glutamate-like substance, which is one of the causative substances of neuropathic diseases represented by Alzheimer's disease. In the field of ophthalmology, NMDA is associated with optic nerve disorders considered to be glaucoma (Brain Research Bulletin, 81 (2010) 349-358). Therefore, this time, NMDA-induced glaucoma model rats were used to evaluate the neuroprotective effect of GGA.

experiment method

For Sprague-Dawley rats, oral administration (Test Example 1), intravitreal administration (Test Example 2), and eye-drop administration (Test Example 3) were carried out. After pre-administration of all-trans, 5Z-mono-cis or teprenone, 5 μL of NMDA was administered to the vitreous to induce neurological disorders. Further, in Test Example 2, as a positive control group, a commercially available glaucoma treatment was administered to the vitreous body. The therapeutic eyedrop Aiphagan (trade name) was administered once a day for 5 days. Further, in each test example, the base containing no GGA or Aiphagan was used as a control group, and the same administration was carried out.

The usage and amount of Test Examples 1 to 3 are shown in Table 1, and the composition of the base used in each test is shown in Table 2.

After the administration of NMDA3, the eyeballs were removed, fixed in semi-Karnovsky (Half Karnovsky) fixative for 24 hours, and then paraffin-embedded and thinly cut to prepare a pathological tissue section stained with hematoxylin-eosin (HE). The tissue sections were observed with an optical microscope, and the thickness (μm) of the intranet (IPL) inside the retina was measured, and the thickness of the intraretinal reticular layer (IPL) was evaluated as an index of the neuroprotective effect of the test preparation.

result

Fig. 7 shows the results of Test Example 1. As shown in Figure 7, when administered orally, the all-trans and 5Z-single forms have neuroprotective effects on NMDA, which are significantly more neuroprotective than the base (*p<0.05, **< 0.01, by Dunnett multiple comparison test). On the other hand, teprenone (all trans-form: 5Z single-cis weight ratio of 6:4) showed no significant neuroprotective effect.

Fig. 8 shows the results of Test Example 2. As shown in Fig. 8, when administered intravitreal, the all-trans and 5Z-single forms have neuroprotective effects against NMDA, which is significantly more neuroprotective than the base (***p<0.001). Tukey-kramer multiple comparison test). In addition, the all-trans-body exhibits a superior superior neuroprotective effect compared to the so-called neuroprotective Aiphagan (trade name) eye drops 0.1% (Qianshou Pharmaceutical) (*p<0.05, by Duke- Kramer multiple comparison check).

Further, Fig. 9 shows a micrograph of the tissue section of Test Example 2.

Fig. 10 shows the results of Test Example 3. From Figure 10, when the eye is administered, the all-trans is a neurological disorder caused by NMDA. The system showed a significant neuroprotective effect compared to the base (*p<0.05, by t-test).

[Industrial availability]

The agent of the present invention is a very useful medicine which can fundamentally prevent, ameliorate or treat retinal diseases by protecting retinal cells from various obstacles, enhancing the function of retinal cells, and inhibiting inflammation of the retina.

The first item of the patent application scope of the present application is a preventive, ameliorating or therapeutic agent for retinal diseases. The diagrams and the photographs showing the results of the examples in the present case are not sufficient to represent the technical features of the present case.

Claims (10)

A prophylactic, ameliorating or therapeutic agent for retinal diseases, which comprises geranylgeranylacetone of 0.00001 to 95% by weight, and the geranylgeranylacetone is (a) only one specific geranyl geranyl group Aromatic geometric isomers, or (b) a mixture of geranylgeranyl azide geometric isomers containing more than 80% by weight of a particular one of the geranylgeranyl geometric isomers. The prophylactic, ameliorating or therapeutic agent for retinal diseases according to the first aspect of the invention, wherein the specific one of the geranylgeranyl acetone geometric isomers is 5Z, 9E, 13E geranyl geranyl group Acetone, 5E, 9Z, 13E geranyl geranylacetone or 5E, 9E, 13Z geranyl geranylacetone. The prophylactic, ameliorating or therapeutic agent for retinal diseases according to the second aspect of the invention, wherein the specific one of the geranylgeranyl acetone geometric isomers is 5Z, 9E, 13E geranyl geranyl group acetone. The prophylactic, ameliorating or therapeutic agent for retinal diseases according to claim 3, wherein the mixture of the geranylgeranylacetone geometric isomers of the (b) is a 5Z, 9E, 13E geranyl scent A mixture of 5Z, 9E, 13E geranylgeranylacetone and 5E, 9E, 13E geranylgeranylacetone of 80% by weight or more of leaf-based acetone. The prophylactic, ameliorating or therapeutic agent for retinal diseases according to any one of claims 1 to 4, which is an ophthalmic preparation. The preventive, ameliorating or therapeutic agent for retinal diseases according to any one of claims 1 to 4, which is an internal drug. The prophylactic, ameliorating or therapeutic agent for retinal diseases according to any one of claims 1 to 6, wherein the retinal disease is one or more selected from the group consisting of glaucoma, retinitis pigmentosa, and age-related macular degeneration. , diabetic retinopathy, retinal detachment, diabetic macular degeneration, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tears, retinal holes, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented vein Pararetinal choroidal atrophy, cerebral gyrus retinal choroidal atrophy, choroidal, crystalline retinopathy, white punctate retinopathy, cone dystrophy, central halo-like choroidal dystrophy, Dorn's honeycomb retinal dystrophy, yolk Macular dystrophy, saccular macular edema, cryptic macular dystrophy, Stargardt disease, retinal detachment, central serous retinal choroidosis, spinocerebellar disorder type 7, familial Exudative vitreoretinopathy, short-wave sensitive cone cell enhancement Syndrome, retinal vascular streak, dominant hereditary optic atrophy, dominant hereditary concealment, acute banded cryptic outer retinopathy, cancerous retinopathy, photodamage, and ischemic retinopathy. Use of a composition for the manufacture of a prophylactic, ameliorating or therapeutic agent for retinal diseases, the composition comprising geranylgeranylacetone 0.00001 to 95% by weight, the geranylgeranylacetone being (a) Only one specific geranylgeranyl azide geometric isomer, or (b) a geranylgeranylacetone geometry containing more than 80% by weight of a specific geranylgeranylacetone geometric isomer A mixture of isomers. A composition for preventing, ameliorating or treating retinal diseases, the composition comprising geranylgeranylacetone 0.00001 to 95% by weight, the geranylgeranylacetone being (a) only one specific species A geranylgeranyl azide geometric isomer, or (b) a geranylgeranylacetone geometric isomer mixture containing more than 80% by weight of a particular geranylgeranyl azide geometrical isomer. A method for preventing, ameliorating or treating a retinal disease, which is a composition for administering a retinal disease, which comprises 0.00001 to 95% by weight of geranylgeranylacetone, and the geranylgeranylacetone is (a) Only one specific geranylgeranyl azide geometric isomer, or (b) a geranylgeranylacetone geometry containing more than 80% by weight of a specific geranylgeranylacetone geometric isomer A mixture of isomers.