JPWO2015029923A1 - Ophthalmic formulation - Google Patents

Abstract

By coexisting (a) geranylgeranylacetone (GGA) and (b) retinal disease therapeutic agent (excluding GGA) in the ophthalmic composition, (b) retinal disease therapeutic agent (excluding GGA) The side effect of conjunctival hyperemia and / or corneal injury due to is suppressed. Further, the cloudiness of the ophthalmic composition and the adsorption of GGA to the container are suppressed. In addition, the stability of GGA to heat and / or light is improved.

Description

  The present invention relates to ophthalmic preparations.

As a therapeutic agent for retinal diseases such as glaucoma, prostaglandin drugs (prostaglandin F2α derivatives), sympathetic nerve blockers, sympathomimetic stimulants, parasympathomimetic stimulants, carbonic anhydrase inhibitors, ROCK inhibitors, etc. A variety of drugs are known.
These drugs improve retinal diseases by suppressing the progression of retinal nerve cell damage, mainly by reducing intraocular pressure.

Typical side effects of therapeutic agents for retinal diseases such as glaucoma include corneal inflammation and corneal disorders such as erosion, eye irritation, conjunctival hyperemia, etc. (Abstracts of Non-Patent Document 1 and Non-Patent Document 2, page 311 right) Column 1-5, page 312 left column 14-18).
Since retinal diseases such as glaucoma are progressive chronic diseases, therapeutic agents are usually used for a long time. Therefore, it is desired to suppress the side effects of these retinal disease therapeutic agents as much as possible.

Here, Patent Document 1 discloses that a specific derivative of prostaglandin A, B, D, E, or F suppresses local side effects of a conventional therapeutic agent for glaucoma and also has an effect of treating glaucoma due to a decrease in intraocular pressure. Is disclosed.
Patent Document 2 further includes an anionic mucus-like polymer and a fine cation exchange resin in addition to a β-blocker that reduces the production of aqueous humor and a glaucoma treatment agent that contains carbachol that increases the outflow of aqueous humor. By doing so, it is disclosed that the side effects of β-blockers and carbachol can be reduced.

JP-A-8-109132 JP-A-5-194271

Ophthalmology Qualify 11, Glaucoma Drug Treatment Guide 2012, 133, 152,153, 163, 171-173, 177 Arch Ophthalmol 126: 309-315, 2008

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

  The present inventor has conducted research in order to solve the above problems, and is a side effect of a retinal disease therapeutic drug by using a retinal disease therapeutic drug in combination with geranylgeranylacetone (hereinafter sometimes referred to as “GGA”). It was found that conjunctival hyperemia and / or corneal injury is suppressed.

  As for GGA, for example, a mixture containing 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetone in a weight ratio of 3: 2 is commercially available under the trade name of Teprenone (Eisai Co., Ltd.). Several animal experiment results suggesting that teprenone (Eisai) acts on retinal cells by oral administration or intraperitoneal administration have been reported (JP 2009-507770, “The American Journal of Pathology, Vol. 178, No. 3, March 2011, 1080-1090 '', `` Investigative Ophthalmology & Visual Science, May 2003, Vol.44, No.5, 1982-1992 '', `` The Journal of Neuroscience, March 2, 2005, 25 (9) , 2396-2404 "," Molecular vision, 2007, 13, 1601-1607 "," Neuroscience Letters, 462, 2009, 281-285 ").

  Here, this inventor discovered that GGA in an ophthalmic formulation is a component which adsorb | sucks to an ophthalmic container remarkably compared with another chemical | medical agent. For example, the amount of adsorbed containers is significantly higher than vitamin A and vitamin E, which are known to be easily adsorbed in containers among the components of ophthalmic preparations. Furthermore, this inventor discovered that adsorption | suction to the ophthalmic container of GGA was suppressed by using GGA and a retinal disease therapeutic agent other than GGA together.

  Further, the ophthalmic preparation is required to have as little turbidity as possible. The present inventor improves the solubility of GGA by using GGA and a therapeutic agent for retinal diseases other than GGA, and the GGA-containing ophthalmology. It was found that the preparation for use became clearer.

  The present inventor has also found that the stability of GGA to heat and light is improved by using GGA in combination with a therapeutic agent for retinal diseases other than GGA.

The present invention has been completed based on the above findings, and provides the following ophthalmic preparations.
Item 1. An ophthalmic preparation comprising (a) geranylgeranylacetone and (b) a retinal disease therapeutic agent (excluding geranylgeranylacetone).
Item 2. Retinal diseases (excluding geranylgeranylacetone) are prostaglandins, sympathetic blockers, sympathomimetics, parasympathomimetics, carbonic anhydrase inhibitors, ROCK inhibitors, calcium antagonists, EP2 Item 2. The ophthalmic preparation according to Item 1, which is one or more selected from the group consisting of an agonist, an adenosine A2a receptor agonist, a VEGF aptamer, and a VEGF inhibitor.
Item 3. Item 3. The ophthalmic preparation according to Item 1 or 2, which is used for prevention, amelioration, or treatment of retinal diseases.
Item 4. Retinal diseases are glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular disease, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tear, retinal hole, macular Hole, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous choroidal atrophy, gyrus reticulochoroidal atrophy, choroideremia, crystal retinopathy, white spot retinopathy, pyramidal dystrophy, central cricoid choroidal dystrophy, Doinbee's focal retinal dystrophy, yolk macular dystrophy, cystic macular edema, occult macular dystrophy, Stargardt's disease, retinoschisis, central serous chorioretinopathy, spinocerebellar degeneration type 7, familial exudative Vitreoretinopathy, S cone augmentation syndrome, retinal pigment streak, autosomal dominant optic atrophy, autosomal dominant drusen, acute occult retinal outer layer disease, cancer-related Endometriosis, photodamage, and ophthalmic preparation according to claim 3 is one or more diseases selected from the group consisting of ischemic retinopathy.
Item 5. Eye drops, intraocular injections, eye ointments, eye washes, contact lens mounting fluids, contact lens fluids, cornea-extracted eye tissue preservatives for transplantation, surgical perfusion fluids, sustained-release intraocular implants, Or the ophthalmic formulation in any one of claim | item 1 -4 which is a sustained release contact lens formulation.
Item 6. Item 6. The ophthalmic preparation according to any one of Items 1 to 5, which is an aqueous composition or an oily composition.
Item 7. Item 7. The ophthalmic preparation according to any one of Items 1 to 6, which is liquid, fluid, gel, or semi-solid.
Item 8. Item 8. The ophthalmic preparation according to any one of Items 1 to 7, wherein a property of congesting the conjunctiva and / or a property of damaging the cornea of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) is suppressed.
Item 9. Item 9. The ophthalmic preparation according to any one of Items 1 to 8, wherein adsorption of geranylgeranylacetone to the container is suppressed.
Item 10. Item 10. The ophthalmic preparation according to any one of Items 1 to 9, wherein white turbidity is suppressed.
Item 11. Item 10. The ophthalmic preparation according to any one of Items 1 to 10, wherein the stability of geranylgeranylacetone to heat and / or light is improved.
Item 12. Item 12. The ophthalmic preparation according to any one of Items 1 to 11, comprising 0.00001 to 90% by weight of geranylgeranylacetone relative to the total amount of the preparation.
Item 13. Item 13. The ophthalmic preparation according to any one of Items 1 to 12, comprising 0.00001 to 90% by weight of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) with respect to the total amount of the preparation.
Item 14. Item 14. The ophthalmic preparation according to any one of Items 1 to 13, comprising 0.0001 to 100,000 parts by weight of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) with respect to 1 part by weight of geranylgeranylacetone.
Item 15. Item 1-14, wherein geranylgeranylacetone and a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) are a combination containing the same composition, or a combination preparation containing geranylgeranylacetone in separate compositions The ophthalmic preparation according to any one of the above.

Item 16. By coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition, (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) ) To suppress the conjunctival hyperemia and / or corneal injury to the ophthalmic composition.
Item 17. A method for suppressing white turbidity of an ophthalmic composition by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in the ophthalmic composition.
Item 18. A method for suppressing adsorption of geranylgeranylacetone to a container by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in an ophthalmic composition.
Item 19. Improve heat and / or light stability of geranylgeranylacetone by coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition. Method.

GGA acts directly on retinal neurons to protect the cells from damage, suppress cell death, and improve survival. In addition, by inducing or promoting cell neurite outgrowth, cell function is improved and damaged retinal cells are regenerated. Therefore, GGA is a drug that enables fundamental treatment of retinal diseases.
On the other hand, therapeutic agents for retinal diseases other than GGA suppress the progression of retinal nerve cell damage by reducing intraocular pressure.
Therefore, the ophthalmic preparation of the present invention protects various retinal cells from degeneration, damage, or death by a multifaceted action, and exhibits remarkable effects in prevention, improvement, or treatment of various retinal diseases. That is, in the ophthalmic preparation of the present invention, the combined use of GGA and other therapeutic agents for retinal diseases significantly improves the prevention, improvement or therapeutic effect of retinal diseases.

  According to the present invention, conjunctival hyperemia and / or corneal injury, which are side effects of retinal disease therapeutic agents other than GGA, are suppressed by using GGA together. Regarding suppression of conjunctival hyperemia, recovery from conjunctival hyperemia may be promoted. In addition, since corneal epithelial damage is known to lead to eye irritation, GGA is considered to suppress eye irritation at the time of instillation with a therapeutic agent for retinal diseases other than GGA. On the other hand, since GGA itself is a widely used drug with established safety, the ophthalmic preparation of the present invention is a drug with excellent safety. Since retinal diseases are progressive chronic diseases, therapeutic agents are generally used for a long time, but the present invention provides an ophthalmic preparation that can be used safely for a long time for the purpose of prevention, improvement or treatment of retinal diseases. It was.

  Further, the ophthalmic preparation of the present invention is remarkably suppressed in the adsorption of GGA to an ophthalmic container (hereinafter also referred to as “container”) and the stability of GGA to heat and light. The amount of GGA inside is maintained. In addition, the range of selection of container materials is widened because of excellent light stability, and management during distribution and storage is easy because of excellent thermal stability.

Further, the ophthalmic preparation of the present invention contains GGA that is difficult to dissolve in water, but its turbidity is kept low. In addition, the ophthalmic preparation of the present invention suppresses white turbidity over time due to storage, particularly storage at low temperatures, by using in combination with a therapeutic agent for retinal diseases other than GGA.
Since the ophthalmic preparation is required to suppress turbidity as much as possible from the viewpoint of uniform dosing and patient preference, the ophthalmic preparation of the present invention with less turbidity is excellent. Moreover, the ophthalmic preparation of the present invention has a wide range of preparations for dissolving GGA, and it is easy to manage distribution and storage in winter and cold regions.

It is a figure which shows the cytoprotective effect by GGA from hypoxia and a low glucose induction ischemia-like cell death. It is a figure which shows the neurite extension induction effect by GGA in rat RGC. It is a figure which shows that GGA suppresses conjunctival hyperemia by a prostaglandin type drug. It is a figure which shows that GGA suppresses conjunctival hyperemia by a ROCK inhibitor. It is a figure which shows that GGA suppresses the cytotoxicity of a beta blocker and a carbonic anhydrase inhibitor.

Hereinafter, the present invention will be described in detail.
The ophthalmic preparation of the present invention contains (a) GGA and (b) a therapeutic agent for retinal diseases other than GGA as active ingredients.

Geranylgeranylacetone (component (a))
(1) Types of geometric isomers GGA has eight types of geometric isomers. Specifically, (5E, 9E, 13E) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5E, 9E, 13EGGA) (all-trans body),
(5Z, 9E, 13E) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9E, 13EGGA) (5Z monocis form),
(5Z, 9Z, 13E) -6,10,14,18-Tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9Z, 13EGGA) (13E monotrans form)
(5Z, 9Z, 13Z) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9Z, 13ZGGA) (all cis form),
(5E, 9Z, 13E) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5E, 9Z, 13EGGA) (9Z monocis),
(5E, 9Z, 13Z) -6,10,14,18-Tetramethyl-5,9,13,17-nonadecatetraen-2-one (5E, 9Z, 13ZGGA) (5E monotrans form)
(5E, 9E, 13Z) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5E, 9E, 13ZGGA) (13Z monocis), and
8 of (5Z, 9E, 13Z) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9E, 13ZGGA) (9E monotrans form) It is a seed.
In addition, the 5Z monocis, 9Z monocis, and 13Z monocis may be collectively referred to as a monocis.

In the present invention, the type of GGA is not limited, and one type can be used alone, or two or more types can be used in any combination.
Among them, in order to exhibit the effect of the present application more remarkably, including all-trans isomers and GGA geometric isomer mixtures containing 80% by weight or more of all-trans isomers (especially all-trans isomers and monocis isomers (especially 5Z monocis isomers)) , A mixture in which the ratio of the all-trans isomer is 80% by weight or more), a monocis isomer, and a GGA geometric isomer mixture (in particular, a monocis isomer (especially a 5Z monocis isomer)) and an all-trans isomer And a mixture of all-trans isomers and 5Z monocis isomers in a weight ratio of 3: 2 is preferred.

  In the GGA geometric isomer mixture containing 80% by weight or more of all-trans isomer, the ratio of all-trans isomer is 80% by weight or more, preferably 82% by weight or more, more preferably 84% by weight or more, and further 86% by weight or more. More preferably, 88 wt% or more is even more preferable, 90 wt% or more is even more preferable, 92 wt% or more is even more preferable, 94 wt% or more is even more preferable, 96 wt% or more is even more preferable, 98 wt% % Or more is even more preferable. If it is the said range, it will come to show a remarkable effect in prevention, improvement, or treatment of a retinal disease.

  Further, in the GGA geometric isomer mixture containing 80% by weight or more of the monocis body, the ratio of the monocis body is 80% by weight or more, preferably 82% by weight or more, more preferably 84% by weight or more, and further 86% by weight or more. More preferably, 88 wt% or more is even more preferable, 90 wt% or more is even more preferable, 92 wt% or more is even more preferable, 94 wt% or more is even more preferable, 96 wt% or more is even more preferable, 98 wt% % Or more is even more preferable. If it is the said range, it will come to show a remarkable effect in prevention, improvement, or treatment of a retinal disease.

  A general-purpose geometric isomer mixture containing an all-trans isomer and a 5Z monocis isomer in a weight ratio of 3: 2 is also preferable because it is easily available.

(2) GGA geometric isomer production method
<All-trans body>
5E, 9E, 13EGGA (all-trans form) has the following structural formula
It is a compound represented by these.
The all-trans body can be purchased from Rionlon, for example.
Further, commercially available teprenone (Eisai Co., Ltd., Wako Pure Chemicals, Yoshindo) can also be obtained by separating it from 5Z monocis by silica gel chromatography using a mobile phase of n-hexane: ethyl acetate = 9: 1, for example. It is done. Separation of the commercially available teprenone 5Z monocis and all-trans isomers can also be performed, for example, by requesting Kobe Natural Products Chemicals.

Furthermore, the all-trans isomer can be synthesized by the method described in Bull. Korean Chem. Soc., 2009, Vol. 30, No. 9, 215-217, for example. In this document, for example, a method shown in the following synthesis scheme is described.
Specifically, in the above reaction formula, geranyl linalool 1, compound 2 and aluminum isopropoxide are mixed, and this mixture is gradually heated to 130 ° C. and reacted. At the end of the reaction, the residual compound 2 is removed and the reaction mixture is diluted with 5% sodium carbonate to quench the residual aluminum propoxide. Thereby, an all-trans form is obtained. Further, the all-trans isomer may be purified by silica gel chromatography using dichloromethane as an eluent.

<Monocis>
5Z, 9E, 13EGGA (5Z monocis) has the following structural formula
It is a compound represented by these.
5Z monocis can be obtained by separation of commercially available teprenone.

<Others>
Other GGA geometric isomers can also be produced by those skilled in the art with reference to the above method.
A mixture of an all-trans isomer and a 5Z monocis isomer containing 80% by weight or more of the all-trans isomer can be obtained by adding the all-trans isomer to commercially available teprenone. A mixture of a 5Z monocis isomer and an all-trans isomer containing 80% by weight or more of the 5Z monocis isomer can be obtained by adding the 5Z monocis isomer to commercially available teprenone.

Reagents for retinal diseases other than component (a) (component (b))
The therapeutic agent for retinal diseases other than GGA (hereinafter sometimes referred to as “retinal disease therapeutic agent”) is not particularly limited. In particular, a therapeutic agent for retinal diseases having side effects such as conjunctival hyperemia and / or corneal disorder is preferable from the standpoint of remarkable effects of the present invention. As a therapeutic agent for retinal diseases other than GGA, more preferably, prostaglandin drugs (prostaglandin F2α derivatives), sympathetic blockers (sympathetic β blockers, sympathetic β1 selective blockers, sympathetic α1 blockers) Sympathetic α2 blockers, sympathetic αβ blockers), sympathomimetics (non-selective stimulators, α2 stimulants), parasympathomimetics (cholinergic agonists, cholinesterase inhibitors), carbonic anhydrase inhibitors, ROCK inhibitors, calcium antagonists, EP2 agonists, adenosine A2a receptor agonists, VEGF aptamers, VEGF inhibitors and the like. Particularly preferred are prostaglandin drugs, sympathetic β-blockers, ROCK inhibitors (Rho kinase inhibitors), and carbonic anhydrase inhibitors.

<Prostaglandin drugs>
Prostaglandin-based retinal disease drugs include, but are not limited to, prost drugs such as latanoprost, travoprost, tafluprost, and bimatoprost (prostamides, prostanoids); such as isopropyl unoprostone Prostone drugs and the like. These are prostaglandin F2α derivatives. Of these, prost drugs are preferable, and latanoprost is particularly preferable.

<Sympathetic blockade>
Sympathetic blockers include, but are not limited to, non-selective β-blockers such as timolol maleate, gelled timolol, carteolol hydrochloride, gelated carteolol; β1-selective β-blockers such as betaxolol hydrochloride An αβ blocker such as levobunolol hydrochloride and nipradilol; an α1 blocker such as bunazosin hydrochloride; Among them, a non-selective β blocker is preferable, and timolol maleate is particularly preferable.

<ROCK inhibitor (Rho kinase inhibitor)>
There are two isoforms of Rho kinase, Rho kinase α / ROKα / ROCK2 and Rho kinase β / ROKβ / ROCK1. In the present invention, the ROCK inhibitor (hereinafter sometimes referred to as “ROCK inhibitor”) may be any of those that inhibit ROCK2, those that inhibit ROCK1, and those that inhibit both. Further, it may be an agent that inhibits other serine / threonine kinases that are activated by the activation of Rho.
ROCK inhibitors include, but are not limited to, Fasudil hydrochloride (Wako Pure Chemical), Y-27632 (Wako Pure Chemical), K-115 (Kowa), SNJ-1656 (Senju Pharmaceutical), AR-12286 (Aerie Pharmaceuticals) ), INS-117548 (Inspire Pharmaceuticals) and the like. Of these, fasudil hydrochloride is preferred.

<Carbonic anhydrase inhibitor (carbonic anhydrase inhibitor)>
Carbonic anhydrase inhibitors include, but are not limited to, acetazolamide, dorzolamide hydrochloride, brinzolamide and the like. Of these, Dorzolamide hydrochloride is preferred.

  Other sympathomimetic agents include epinephrine, epinephrine hydrogen tartrate, dipivefrin hydrochloride, brimonidine tartrate, etc., parasympathomimetic agents include pilocarpine hydrochloride, distigmine bromide and the like, and calcium antagonists include Romeridine hydrochloride and the like, EP2 agonists include DE-117, etc., adenosine A2a receptor agonists include OPA-6656, and VEGF aptamers include pegaptanib sodium and the like. Examples of VEGF inhibitors include ranibizumab and bevacizumab.

  The retinal disease therapeutic agent selected from the group consisting of prostaglandin drugs, sympathetic β-blockers, ROCK inhibitors, and carbonic anhydrase inhibitors can be used alone or in combination of two or more. When two or more kinds are combined, two or more kinds of drugs of the same strain, for example, prostaglandin drugs may be combined, or different kinds of drugs, for example, prostaglandin drugs and sympathetic β-blockers may be combined. Good.

As a combination of GGA and a prostaglandin drug, a sympathetic β-blocker, a ROCK inhibitor, and a retinal disease therapeutic agent selected from the group consisting of carbonic anhydrase inhibitors,
Combinations of GGA and prostaglandins such as GGA and latanoprost, GGA and travoprost, GGA and tafluprost, GGA and bimatoprost A combination of GGA and a prostone drug such as a combination of GGA and isopropyl unoprostone),
Combinations of GGA and sympatholytic agents (GGA such as combination of GGA and timolol maleate, combination of GGA and gelled timolol, combination of GGA and carteolol hydrochloride, combination of GGA and gelled carteolol A combination of GGA and β1-selective β-blocker, such as a combination of GGA and betaxolol hydrochloride; a combination of GGA and levobunolol hydrochloride, a combination of GGA and nipradilol Combination of GGA and αβ blocker),
A combination of GGA and fasudil hydrochloride, a combination of GGA and Y-27632, a combination of GGA and K-115, a combination of GGA and SNJ-1656, a combination of GGA and AR-12286, a combination of GGA and INS-117548 A combination of GGA and ROCK inhibitor, such as
A combination of GGA and acetazolamide, a combination of GGA and dorzolamide hydrochloride, a combination of GGA and a carbonic anhydrase inhibitor, such as a combination of GGA and brinzolamide, and the like.
Also, combinations of GGA, latanoprost and timolol maleate, combinations of GGA, latanoprost and gelled timolol, combinations of GGA, travoprost and timolol maleate, combinations of GGA, travoprost and gelled timolol A combination of GGA, a prostaglandin and a sympathetic beta-blocker,
A combination of GGA, a sympathetic β-blocker, and a carbonic anhydrase inhibitor, such as a combination of GGA, timolol maleate, and dorzolamide hydrochloride, and a combination of GGA, gelled timolol, and dorzolamide hydrochloride are also included.

The properties of the pharmaceutical ophthalmic formulation are not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid. In addition, liquids, fluids, gels, semi-solids, or solids that have been prepared upon use are also included. The semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment.

  The type of ophthalmic preparation is not particularly limited. For example, eye drops (including eye drops when wearing contact lenses), eye wash, contact lens mounting liquid, contact lens liquid (cleaning liquid, preservative liquid, disinfecting liquid, multipurpose solution, package solution), transplant cornea, etc. Preservatives for isolated ocular tissues, perfusate during surgery, ointment (water-soluble ointment, oil-soluble ointment), intraocular injection (eg, intravitreal injection), sustained-release intraocular implant, and Examples include sustained-release contact lens preparations. Of these, eye drops, intraocular injections, eye ointments, and eye washes are preferable, and eye drops are more preferable in terms of good transferability to the affected area.

In addition, the ophthalmic agent may be an aqueous composition (mainly including an aqueous or hydrophilic base or carrier), and an oily composition (an oil or hydrophobic base or carrier is mainly used). Included).
The content of water in the case of the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the preparation. In addition, the base or carrier may be composed only of water.
The content of water in the case of an oily composition is preferably 50% by weight or less, more preferably 30% by weight or less, and still more preferably 20% by weight or less based on the total amount of the preparation.

  Methods for preparing ophthalmic formulations are well known. GGA is a pharmaceutically acceptable base or carrier, if necessary, pharmaceutically acceptable additives for ophthalmic preparations, and other active ingredients (physiologically active ingredients or pharmacologically active ingredients other than GGA). It can be prepared by mixing with.

<Base or carrier>
Examples of the base or carrier include water; aqueous solvents such as polar solvents; polyhydric alcohols; vegetable oils; Examples of the base or carrier for intraocular injection include distilled water for injection and physiological saline.
A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

<Additives>
Examples of additives include surfactants, fragrances or refreshing agents, preservatives, bactericides or antibacterial agents, pH adjusting agents, isotonic agents, chelating agents, buffering agents, stabilizers, antioxidants, and Examples thereof include a thickening agent. Intraocular injections may contain solubilizers, suspending agents, isotonic agents, buffers, soothing agents, stabilizers, preservatives, and the like.
An additive can be used individually by 1 type or in combination of 2 or more types.

Specific examples of the additive 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 block copolymer adduct of ethylenediamine (for example, poloxamine), POE sorbitan fatty acid ester (for example, polysorbate 20, polysorbate 60, polysorbate 80 (TO-10, etc.)), POE hydrogenated castor oil (for example, POE (60) cured) Castor oil (such as HCO-60)), POE castor oil, POE alkyl ethers (eg, polyoxyethylene (9) lauryl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether), and stearin Nonionic surfactants such as polyoxyl;
Amphoteric surfactants such as glycine-type amphoteric surfactants (eg, alkyldiaminoethylglycine, alkylpolyaminoethylglycine) and betaine-type amphoteric surfactants (eg, lauryldimethylaminoacetic acid betaine, imidazolinium betaine); Cationic surfactants such as alkyl quaternary ammonium salts (for example, benzalkonium chloride, benzethonium chloride).
The numbers in parentheses indicate the number of added moles.
Perfume or refreshing agent: for example, camphor, borneol, terpenes (which may be d-form, l-form or dl-form), mint water, eucalyptus oil, bergamot oil, anethole, eugenol, geraniol, menthol, limonene, Essential oils such as peppermint oil, peppermint oil, and rose oil.

  Preservatives, bactericides or antibacterials: for example, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride) , And glow kill (made by Rhodia).

  pH adjuster: For example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  Chelating agents: for example, ascorbic acid, edetate tetrasodium, edetate sodium, and citric acid.

  Buffers: For example, phosphate buffers; citrate buffers such as citric acid and sodium citrate; acetate buffers such as acetic acid, potassium acetate and sodium acetate; carbonate buffers such as sodium bicarbonate and sodium carbonate Boric acid buffers such as boric acid and borax; taurine, aspartic acid and salts thereof (such as potassium salt), amino acid buffers such as epsilon-aminocaproic acid, and the like.

Among them, it is preferable to adjust the pH using a phosphate buffer, whereby the adsorption of GGA to the container wall and thus the decrease in the content of GGA in the ophthalmic preparation is further suppressed. Further, white turbidity during storage at a low temperature is further suppressed, adsorption of GGA to the contact lens is suppressed, and an effect that stability against heat and light is further improved can be obtained.
A phosphate buffer can be used individually by 1 type or in combination of 2 or more types.
The phosphate buffer is not particularly limited. For example, phosphoric acid; disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate Alkali metal salts of phosphoric acid such as: calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimagnesium phosphate (magnesium hydrogen phosphate), alkalis of phosphoric acid such as trimagnesium phosphate Earth metal salts; ammonium salts of phosphoric acid such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate. The phosphate buffer may be either an anhydride or a hydrate.

Among these, it is preferable to use at least one selected from the group consisting of phosphoric acid and alkali metal salts of phosphoric acid, and more preferable to use at least one selected from the group consisting of phosphoric acid and sodium salt of phosphoric acid. preferable.
As a preferable combination of the phosphate buffer, a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate, a combination of phosphoric acid, disodium hydrogen phosphate and sodium dihydrogen phosphate, Combination of phosphoric acid, disodium hydrogen phosphate and trisodium phosphate, combination of phosphoric acid, sodium dihydrogen phosphate and trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate Combinations of, phosphoric acid and disodium hydrogen phosphate, phosphoric acid and sodium dihydrogen phosphate, phosphoric acid and trisodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate In combination with disodium hydrogen phosphate and trisodium phosphate As combinations of sodium dihydrogen phosphate and phosphoric acid trisodium.
Among them, a combination of phosphoric acid, disodium hydrogen phosphate and sodium dihydrogen phosphate, a combination of phosphoric acid and disodium hydrogen phosphate, a combination of phosphoric acid and sodium dihydrogen phosphate, disodium hydrogen phosphate and A combination with sodium dihydrogen phosphate is preferred, and a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is more preferred.

The content of the phosphate buffer is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and further preferably 0.01% by weight or more, based on the total amount of the preparation, in terms of anhydride. More preferably, 0.05% by weight or more is even more preferable. If it is the said range, the stabilization effect of GGA, the low-temperature white turbidity suppression effect, and the adsorption | suction suppression effect to the container wall and contact lens of GGA by the phosphate buffer addition will fully be acquired.
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, and more preferably 5% by weight or less based on the total amount of the preparation in terms of anhydride. Even more preferred is 3% by weight or less. If it is the said range, there is little irritation | stimulation to eyes.

  The phosphate buffer content is about 0.001 to 10% by weight, about 0.001 to 7% by weight, and about 0.001 to 5% by weight, based on the total amount of the formulation, in terms of anhydride. About 0.001 to 3 wt%, about 0.005 to 10 wt%, about 0.005 to 7 wt%, about 0.005 to 5 wt%, about 0.005 to 3 wt%, about 0.01 10 wt%, about 0.01-7 wt%, about 0.01-5 wt%, about 0.01-3 wt%, about 0.05-10 wt%, about 0.05-7 wt%, About 0.05 to 5 weight%, about 0.05 to 3 weight% is mentioned.

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, and more preferably 0.005 parts by weight with respect to 1 part by weight of GGA in terms of anhydride. Part or more is even more preferable, and 0.01 part by weight or more is even more preferable. If it is the said range, the stabilization effect of GGA, the low-temperature white turbidity suppression effect, and the adsorption | suction suppression effect to the container wall and contact lens of GGA by the phosphate buffer addition will fully be acquired.
Further, the content of the phosphate buffer is preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, and even more preferably 500 parts by weight or less with respect to 1 part by weight of GGA in terms of anhydride. 200 parts by weight or less is even more preferable. If it is the said range, there is little irritation | stimulation to eyes.

  The content of the phosphate buffer is about 0.0005 to 5000 parts by weight, about 0.0005 to 1000 parts by weight, and about 0.0005 to 500 parts per 1 part by weight of GGA in terms of anhydride. Parts by weight, about 0.0005 to 200 parts by weight, 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 0.005-5000 parts by weight, about 0.005-1000 parts by weight, about 0.005-500 parts by weight, about 0.005-200 parts by weight, about 0.01-5000 parts by weight, about 0.01-1000 parts by weight Parts, about 0.01 to 500 parts by weight, and about 0.01 to 200 parts by weight.

  When the preparation of the present invention is a combination agent of two or more types, it is preferable that a phosphate buffer is contained in the composition containing GGA. In this case, the content of the phosphate buffer is an amount in the composition containing GGA.

  Stabilizers: trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate and the like.

  Antioxidants: Ascorbic acid, ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2-sodium phosphate, etc.), sodium bisulfite, sodium sulfite Water-soluble antioxidants such as sodium thiosulfate.

The ophthalmic preparation may contain a fat-soluble antioxidant, which further suppresses the adsorption of the ophthalmic agent to the container wall and consequently the decrease in the content of GGA in the composition. Further, the adsorption of GGA to the contact lens is suppressed, and the stability of GGA to heat and light is further improved.
Examples of the fat-soluble antioxidant include butyl group-containing phenols such as butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbate stearate, Ascorbic acid esters such as aminopropyl ascorbate phosphate, tocopherol ascorbate phosphate, ascorbyl triphosphate, ascorbyl phosphate palmitate; tocopherols such as α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol; Tocopherol derivatives such as tocopherol acetate, tocopherol nicotinate, tocopherol succinate; ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate Gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2one; vegetable oils such as soybean oil, rapeseed oil, olive oil, sesame oil; carotenoids such as lutein, astaxanthin; anthocyanins, catechin, tannin, Polyphenols such as curcumin; retinol, retinol esters (retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, palmitate Acid retinol), retinal, retinal ester (retinal acetate, retinal propionate, retinal palmitate, etc.), retinoic acid, retinoic acid ester (retinoic acid) Methyl acetate, ethyl retinoate, retinol retinoic acid, tocopherol retinoic acid, etc.), retinol dehydro, retinal dehydro, retinoic dehydro, provitamin A (α-carotene, β-carotene, γ-carotene, δ-carotene) , Lycopene, zeaxanthin, β-cryptoxanthin, echinone, etc.), vitamin A such as vitamin A; CoQ10 and the like. These compounds are commercially available.
Of these, butyl group-containing phenol, NDGA, ascorbic acid ester, tocopherol, tocopherol derivative, gallic acid ester, propyl gallate, 3-butyl-4-hydroxyquinolin-2-one, vegetable oil, and vitamin A are preferable. Of these, butyl group-containing phenols, tocopherols, tocopherol derivatives, vegetable oils and vitamin A are preferred, butyl group-containing phenols, vegetable oils, retinol or retinol esters are more preferred, and BHT, BHA, sesame oil, and retinol palmitate are even more preferred.
The fat-soluble antioxidant can 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, and even more preferably 0.0001% by weight or more based on the total amount of the preparation. Preferably, 0.0005% by weight or more is even more preferable. If it is the said range, the GGA adsorption | suction suppression effect (suppression effect of the content rate reduction of GGA) to the container wall by addition of a fat-soluble antioxidant, the GGA adsorption | suction suppression effect to a contact lens, and the heat | fever and light of GGA The effect of improving the stability against the above can be sufficiently obtained.
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, based on the total amount of the preparation. % Or less is even more preferable. Within the above range, there is little eye irritation.

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

The content of the fat-soluble antioxidant in the ophthalmic preparation is preferably 0.0001 parts by weight or more, more preferably 0.001 parts by weight or more, and 0.005 parts by weight with respect to 1 part by weight of GGA. The above is even more preferable, and 0.01 parts by weight or more is even more preferable. If it is the said range, the GGA adsorption | suction suppression effect (suppression effect of the content rate reduction of GGA) to the container wall by addition of a fat-soluble antioxidant, the GGA adsorption | suction suppression effect to a contact lens, and the heat | fever and light of GGA The effect of improving the stability against the above can be sufficiently obtained.
Further, the content of the fat-soluble antioxidant in the ophthalmic agent 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, relative to 1 part by weight of GGA. Even more preferably 5 parts by weight or less. If it is the said range, there is also little irritation | stimulation to eyes.

  The content of the fat-soluble antioxidant in the ophthalmic preparation is about 0.0001 to 100 parts by weight, about 0.0001 to 50 parts by weight, and about 0.0001 to 10 parts by weight with respect to 1 part by weight of GGA. Parts, about 0.0001-5 parts by weight, about 0.001-100 parts by weight, about 0.001-50 parts by weight, about 0.001-10 parts by weight, about 0.001-5 parts by weight, about 0.001. 005-100 parts by weight, about 0.005-50 parts by weight, about 0.005-10 parts by weight, about 0.005-5 parts by weight, about 0.01-100 parts by weight, about 0.01-50 parts by weight , About 0.01 to 10 parts by weight, and about 0.01 to 5 parts by weight.

  When the preparation of the present invention is a two-component or more concomitant agent, the composition containing GGA preferably contains a fat-soluble antioxidant. In this case, the content of the fat-soluble antioxidant is an amount in the composition containing GGA.

  Thickening agent: guar gum, hydroxypropyl guar gum, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, cellulose polymer such as sodium carboxymethylcellulose, gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, Dextrin, dextran, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, hyaluronate (sodium salt, etc.), chondroitin sulfate sodium, starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinylpyrrolidone, polyvinyl Alcohol, polyvinyl polymer such as polyvinyl methacrylate, polyacryl Alkali metal salts (such as sodium salt and potassium salt), polyacrylic acid amine salts (monoethanolamine salt, diethanolamine salt, triethanolamine salt etc.), carboxyvinyl polymers such as ammonium salt of polyacrylic acid, casein Gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (such as sodium salt), alginate (such as propylene glycol ester), tragacanth powder, and triisopropanolamine.

<Other pharmacologically active ingredients or physiologically active ingredients>
The ophthalmic preparation may contain a pharmacologically active ingredient or a physiologically active ingredient other than the preventive, ameliorative, or therapeutic ingredient for retinal diseases. Such pharmacologically active ingredients or physiologically active ingredients can be used singly or in combination of two or more.
As such pharmacologically active components and physiologically active components, neurotrophic factor, decongestant component, ocular muscle modulator component, anti-inflammatory component or astringent component, antihistamine component or antiallergic component, vitamins, amino acids , Antibacterial or bactericidal components, saccharides, polymer compounds, cellulose or derivatives thereof, and local anesthetic components. Specific examples of these drugs are illustrated below.

Neurotrophic factor: Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and the like.
Moreover, since serum contains nutrient factors including neurotrophic factor, it is possible to add a serum collected from a patient to prepare a preparation for use in the patient.

  Decongestant: for example, α-adrenergic agonist, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and naphazoline nitrate . These may be d-form, l-form or dl-form.

  Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, Diclofenac sodium, bromfenac sodium, berberine chloride, and berberine sulfate.

  Antihistamine component or antiallergic agent component: for example, salt such as acitazanolast, diphenhydramine or its hydrochloride, chlorpheniramine maleate, ketotifen fumarate, levocabastine or its hydrochloride, etc., anlexanox, ibudilast, tazanolast, tranilast, Salts such as oxatomide, suplatast or its tosylate, sodium cromoglycate, and pemirolast potassium.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol nicotinate, succinic acid Tocopherol, calcium tocopherol succinate, and ubiquinone derivatives.

  Amino acids: For example, aminoethyl sulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine, alanine Arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: for example, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxa Zole monoethanolamine, sodium sulfisomezole, sodium sulfisomidine, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir.

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

  Macromolecular compounds: for example, alginic acid, sodium alginate, dextrin, dextran, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, carboxyvinyl polymer, macrogol and its pharmaceutically acceptable Such as salt.

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

  Local anesthetic components: for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, etc.

Sustained release intraocular implants As examples of ophthalmic preparations, sustained release intraocular implants can also be mentioned. Various methods for preparing sustained-release intraocular implants are known. For example, a matrix preparation obtained by mixing GGA and / or a therapeutic agent for retinal diseases other than GGA with a carrier containing a polymer substance, and a core containing a therapeutic agent for retinal diseases other than GGA and / or GGA are coated with a polymer film. Examples of the preparation include capsule preparations in which GGA and / or a therapeutic agent for retinal diseases other than GGA are encapsulated in fine capsules made of a polymer substance.
As the polymer, polymers used for sustained-release intraocular implants can be used without limitation. For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, pullulan, gelatin, collagen, atelocollagen, hyaluronic acid Casein, agar, gum arabic, dextrin, ethyl cellulose, methyl cellulose, chitin, chitosan, mannan, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, sodium alginate, polyvinyl alcohol, cellulose acetate, polyvinyl pyrrolidone, silicone, polyvinyl acetal diethylaminoacetate, Examples include albumin and lactic acid / glycolic acid copolymer.
One type of polymer can be used alone, or two or more types can be used in combination.
The sustained-release intraocular implant can contain pharmacologically active components or physiologically active components other than the retinal disease therapeutic agent. As this component, for example, those exemplified above can be used. The sustained-release intraocular implant is not limited to a solid, and can take properties such as semi-solid, gel, fluid, and liquid.

Sustained-release contact lens preparations Examples of ophthalmic preparations include sustained-release contact lens preparations in which the contact lens itself contains GGA and / or a therapeutic agent for retinal diseases other than GGA. Such sustained-release preparations can be used in contact lens solutions containing, for example, GGA and / or retinal disease therapeutic agents other than GGA, such as cleaning solutions, storage solutions, disinfectants, multipurpose solutions, package solutions, etc. Can be prepared by soaking. Or contact lens manufacturing raw materials, for example, contact lens polymer constituent monomers (hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, ethylene glycol dimethacrylate, benzoin methyl ether, etc.), colorants, or ultraviolet absorbers After impregnating with GGA and / or a therapeutic agent for retinal diseases other than GGA, a contact lens can be prepared using them.

The sustained-release contact lens preparation can contain a pharmacologically active ingredient or a physiologically active ingredient other than the retinal disease therapeutic agent. As this component, for example, those exemplified above can be used.
The sustained-release intraocular implant and the sustained-release contact lens preparation may contain both GGA and a therapeutic agent for retinal diseases other than GGA, or may contain only one of them. When only one is contained, an ophthalmic preparation containing the other may be applied separately to the eye.

<Content of GGA>
The content of GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, more preferably 0.00005% by weight or more based on the total amount of the composition. 0.0008 wt% or more is more preferable, 0.0001 wt% or more is more preferable, 0.0003 wt% or more is more preferable, 0.0005 wt% or more is more preferable, 0.0008 wt% or more is more preferable, 0 0.001% by weight or more is even more preferable. Further, it may be 0.003% by weight or more, 0.005% by weight or more, 0.008% by weight or more, 0.01% by weight or more, It may be 0.03% by weight or more, 0.05% by weight or more, 0.08% by weight or more, 0.1% by weight or more, It may be 3% by weight or more, 0.5% by weight or more, 0.8% by weight or more, or 1% by weight or more. Within the above range, conjunctival hyperemia and corneal injury due to the component (b) are sufficiently suppressed, and the prevention, improvement, or treatment effect of retinal diseases is sufficiently obtained.
In addition, the content of GGA in the ophthalmic preparation is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 30% by weight or less with respect to the total amount of the preparation. Moreover, 10 weight% or less may be sufficient. If it is the said range, while being able to fully obtain the prevention, improvement, or treatment effect of a retinal disease, it will become a clearer formulation which is hard to produce fog vision.
In particular, when the ophthalmic preparation is a preparation other than a solid preparation, for example, a liquid form, a fluid form, a gel form, or a semi-solid form, the content of GGA in the preparation is based on the total amount of the preparation. Is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less, and even more preferably 2% by weight or less.

  The content of GGA in the ophthalmic preparation is about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 30% by weight, about 0.0. 00001-10 wt%, about 0.00003-90 wt%, about 0.00003-50 wt%, about 0.00003-30 wt%, about 0.00003-10 wt%, about 0.00005-90 wt% About 0.00005 to 50 wt%, about 0.00005 to 30 wt%, about 0.00005 to 10 wt%, about 0.00008 to 90 wt%, about 0.00008 to 50 wt%, about 0.00008 -30 wt%, about 0.00008-10 wt%, about 0.0001-90 wt%, about 0.0001-50 wt%, about 0.0001-30 wt%, about 0.0001-10 wt%, About 0.0003 90 wt%, about 0.0003-50 wt%, about 0.0003-30 wt%, about 0.0003-10 wt%, about 0.0005-90 wt%, about 0.0005-50 wt%, about 0.0005-30 wt%, about 0.0005-10 wt%, about 0.0008-90 wt%, about 0.0008-50 wt%, about 0.0008-30 wt%, about 0.0008-10 %, About 0.001 to 90%, about 0.001 to 50%, about 0.001 to 30%, about 0.001 to 10%, about 0.003 to 90%, about 0% 0.003 to 50 wt%, about 0.003 to 30 wt%, about 0.003 to 10 wt%, about 0.005 to 90 wt%, about 0.005 to 50 wt%, about 0.005 to 30 wt% %, About 0.005 to 10% by weight, about 0.008 to 90% by weight, about 0. 08-50 wt%, about 0.008-30 wt%, about 0.008-10 wt%, about 0.01-90 wt%, about 0.01-50 wt%, about 0.01-30 wt% About 0.01 to 10 wt%, about 0.03 to 90 wt%, about 0.03 to 50 wt%, about 0.03 to 30 wt%, about 0.03 to 10 wt%, about 0.05 -90 wt%, about 0.05-50 wt%, about 0.05-30 wt%, about 0.05-10 wt%, about 0.08-90 wt%, about 0.08-50 wt%, About 0.08 to 30 wt%, about 0.08 to 10 wt%, about 0.1 to 90 wt%, about 0.1 to 50 wt%, about 0.1 to 30 wt%, about 0.3 to 90% by weight, about 0.3-50% by weight, about 0.3-30% by weight, about 0.3-10% by weight, about 0.5-90% by weight, about 0.5-50% by weight, about 0.5-30 %, About 0.5 to 10%, about 0.8 to 90%, about 0.8 to 50%, about 0.8 to 30%, about 0.8 to 10%, about 1 -90 wt%, about 1-50 wt%, about 1-30 wt%, about 1-10 wt%.

  In particular, when the ophthalmic preparation is a preparation other than a solid preparation, for example, a liquid form, a fluid form, a gel form, or a semi-solid form, the content of GGA in the preparation is relative to the total amount of the preparation. About 0.00001 to 10% by weight, about 0.00001 to 5% by weight, about 0.00001 to 3% by weight, about 0.00001 to 2% by weight, about 0.00003 to 10% by weight, about 0.0. 00003-5 wt%, about 0.00003-3 wt%, about 0.00003-2 wt%, about 0.00005-10 wt%, about 0.00005-5 wt%, about 0.00005-3 wt% About 0.00005 to 2 wt%, about 0.00008 to 10 wt%, about 0.00008 to 5 wt%, about 0.00008 to 3 wt%, about 0.00008 to 2 wt%, about 0.0001 -10 wt%, about 0.0001-5 wt% About 0.0001 to 3 wt%, about 0.0001 to 2 wt%, about 0.0003 to 10 wt%, about 0.0003 to 5 wt%, about 0.0003 to 3 wt%, about 0.0003 to 2 wt%, about 0.0005 to 10 wt%, about 0.0005 to 5 wt%, about 0.0005 to 3 wt%, about 0.0005 to 2 wt%, about 0.0008 to 10 wt%, about 0.0008 to 5 wt%, about 0.0008 to 3 wt%, about 0.0008 to 2 wt%, about 0.001 to 10 wt%, about 0.001 to 5 wt%, about 0.001 to 3 %, About 0.001 to 2%, about 0.003 to 10%, about 0.003 to 5%, about 0.003 to 3%, about 0.003 to 2%, about 0% 0.005 to 10 wt%, about 0.005 to 5 wt%, about 0.005 to 3 wt%, about 0.005 to 2 wt%, 0.008-10 wt%, about 0.008-5 wt%, about 0.008-3 wt%, about 0.008-2 wt%, about 0.01-10 wt%, about 0.01-5 %, About 0.01 to 3%, about 0.01 to 2%, about 0.03 to 10%, about 0.03 to 5%, about 0.03 to 3%, about 0% 0.03 to 2 wt%, about 0.05 to 10 wt%, about 0.05 to 5 wt%, about 0.05 to 3 wt%, about 0.05 to 2 wt%, about 0.08 to 10 wt% %, About 0.08 to 5% by weight, about 0.08 to 3% by weight, about 0.08 to 2% by weight, about 0.1 to 10% by weight, about 0.1 to 5% by weight, about 0. 1-3 wt%, about 0.1-2 wt%, about 0.3-10 wt%, about 0.3-5 wt%, about 0.3-3 wt%, about 0.3-2 wt% About 0.5 to 10 wt%, about 0.5 to 5 wt%, about 0 .5-3% by weight, about 0.5-2% by weight, about 0.8-10% by weight, about 0.8-5% by weight, about 0.8-3% by weight, about 0.8-2% by weight %, About 1-10% by weight, about 1-5% by weight, about 1-3% by weight, about 1-2% by weight.

  Further, when the ophthalmic preparation is a solid preparation, the content of GGA in the preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and even more preferably 0.1 mg or more in the whole preparation. If it is the said range, while the prevention, improvement, or therapeutic effect of a retinal disease will fully be acquired, the side effect by retinal disease therapeutic agents other than GGA will fully be suppressed. Further, the content of GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less in the whole preparation. If it is the said range, the prevention, improvement, or therapeutic effect of a retinal disease will fully be acquired.

  The content of GGA in the solid preparation is 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 with respect to the total amount of the preparation. -100 mg, about 0.01-10 mg, about 0.1-1000 mg, about 0.1-100 mg, about 0.1-10 mg.

<Content of retinal disease therapeutic agents other than GGA>
The content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, and 0.00005% by weight or more with respect to the total amount of the preparation. Is more preferably 0.00008% by weight or more, more preferably 0.0001% by weight or more, more preferably 0.0003% by weight or more, and even more preferably 0.0005% by weight or more. Further, it may be 0.0008% by weight or more, 0.001% by weight or more, 0.003% by weight or more, 0.005% by weight or more, It may be 0.008% by weight or more, 0.01% by weight or more, 0.03% by weight or more, 0.05% by weight or more, It may be 08% by weight or more, or 0.1% by weight or more. If it is the said range, each effect of container adsorption | suction suppression of GGA, white turbidity suppression of a formulation, the heat | fever and light stability improvement of GGA is fully acquired, and the prevention, improvement, or therapeutic effect of retinal disease is fully acquired. .
Further, the content of the therapeutic agent for retinal diseases other than GGA is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 10% by weight or less based on the total amount of the preparation. It may be 5% by weight or less, or 1% by weight or less. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.

  The content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 10% with respect to the total amount of the preparation. %, About 0.00001-5%, about 0.00001-1%, about 0.00003-90%, about 0.00003-50%, about 0.00003-10%, about 0% 0.00003-5 wt%, about 0.00003-1 wt%, about 0.00005-90 wt%, about 0.00005-50 wt%, about 0.00005-10 wt%, about 0.00005-5 wt% %, About 0.00005 to 1%, about 0.00008 to 90%, about 0.00008 to 50%, about 0.00008 to 10%, about 0.00008 to 5%, about 0.0. 00008 to 1% by weight, approx. 0.0001 to 90 wt%, about 0.0001 to 50 wt%, about 0.0001 to 10 wt%, about 0.0001 to 5 wt%, about 0.0001 to 1 wt%, about 0.0003 to 90 wt% %, About 0.0003-50 wt%, about 0.0003-10 wt%, about 0.0003-5 wt%, about 0.0003-1 wt%, about 0.0005-90 wt%, about 0.0. 0005-50 wt%, about 0.0005-10 wt%, about 0.0005-5 wt%, about 0.0005-1 wt%, about 0.0008-90 wt%, about 0.0008-50 wt% , About 0.0008 to 10 wt%, about 0.0008 to 5 wt%, about 0.0008 to 1 wt%, about 0.001 to 90 wt%, about 0.001 to 50 wt%, about 0.001 -10 wt%, about 0.001-5 wt%, about 0.001-1 wt% About 0.003 to 90 wt%, about 0.003 to 50 wt%, about 0.003 to 10 wt%, about 0.003 to 5 wt%, about 0.003 to 1 wt%, about 0.005 90 wt%, about 0.005 to 50 wt%, about 0.005 to 10 wt%, about 0.005 to 5 wt%, about 0.005 to 1 wt%, about 0.008 to 90 wt%, about 0.008-50% by weight, about 0.008-10% by weight, about 0.008-5% by weight, about 0.008-1% by weight, about 0.01-90% by weight, about 0.01-50 %, About 0.01 to 10%, about 0.01 to 5%, about 0.01 to 1%, about 0.03 to 90%, about 0.03 to 50%, about 0% 0.03 to 10 wt%, about 0.03 to 5 wt%, about 0.03 to 1 wt%, about 0.05 to 90 wt%, about 0.05 to 50 wt%, about 0.0 5-10% by weight, about 0.05-5% by weight, about 0.05-1% by weight, about 0.08-90% by weight, about 0.08-50% by weight, about 0.08-10% by weight About 0.08 to 5 wt%, about 0.08 to 1 wt%, about 0.1 to 90 wt%, about 0.1 to 50 wt%, about 0.1 to 10 wt%, about 0.1 -5% by weight, about 0.1-1% by weight.

The content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.0001 parts by weight or more, more preferably 0.0003 parts by weight or more, and 0.0005 parts by weight with respect to 1 part by weight of GGA. More preferably, 0.0008 parts by weight or more, more preferably 0.001 parts by weight or more, more preferably 0.003 parts by weight or more, more preferably 0.005 parts by weight or more, and 0.008 parts by weight. The above is more preferable, and 0.01 parts by weight or more is even more preferable. Moreover, 0.1 weight part or more may be sufficient. If it is the said range, while each effect of the container adsorption | suction suppression of GGA, the cloudiness suppression of a composition, and the heat | fever and light stability improvement of GGA is fully acquired, the prevention, improvement, or therapeutic effect of retinal disease will fully be acquired. It is done.
The content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 100000 parts by weight or less, more preferably 8000 parts by weight or less, and more preferably 5000 parts by weight or less with respect to 1 part by weight of GGA. 3000 parts by weight or less is more preferable, 1000 parts by weight or less is more preferable, 800 parts by weight or less is more preferable, 500 parts by weight or less is more preferable, 300 parts by weight or less is more preferable, and 100 parts by weight or less is even more preferable. Moreover, 10 weight part or less may be sufficient. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.

  The content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is about 0.0001 to 100,000 parts by weight, about 0.0001 to 8000 parts by weight, about 0.0001 to about 1 part by weight of GGA. 5000 parts by weight, about 0.0001 to 3000 parts by weight, about 0.0001 to 1000 parts by weight, about 0.0001 to 800 parts by weight, about 0.0001 to 500 parts by weight, about 0.0001 to 300 parts by weight, about 0.0001-100 parts by weight, about 0.0001-10 parts by weight, about 0.0003-100000 parts by weight, about 0.0003-8000 parts by weight, about 0.0003-5000 parts by weight, about 0.0003-3000 Parts by weight, about 0.0003 to 1000 parts by weight, about 0.0003 to 800 parts by weight, about 0.0003 to 500 parts by weight, about 0.0003 to 300 parts by weight, about 0.0003 to 00 parts by weight, about 0.0003 to 10 parts by weight, about 0.0005 to 100000 parts by weight, about 0.0005 to 8000 parts by weight, about 0.0005 to 5000 parts by weight, about 0.0005 to 3000 parts by weight, about 0.0005 to 1000 parts by weight, about 0.0005 to 800 parts by weight, about 0.0005 to 500 parts by weight, about 0.0005 to 300 parts by weight, about 0.0005 to 100 parts by weight, about 0.0005 to 10 Parts by weight, about 0.0008-100000 parts by weight, about 0.0008-8000 parts by weight, about 0.0008-5000 parts by weight, about 0.0008-3000 parts by weight, about 0.0008-1000 parts by weight, about 0 parts by weight .0008 to 800 parts by weight, about 0.0008 to 500 parts by weight, about 0.0008 to 300 parts by weight, about 0.0008 to 100 parts by weight, about 0.0008 to 10 parts by weight, 0.001 to 100000 parts by weight, about 0.001 to 8000 parts by weight, about 0.001 to 5000 parts by weight, about 0.001 to 3000 parts by weight, about 0.001 to 1000 parts by weight, about 0.001 to 800 parts Parts by weight, about 0.001 to 500 parts by weight, about 0.001 to 300 parts by weight, about 0.001 to 100 parts by weight, about 0.001 to 10 parts by weight, about 0.003 to 100000 parts by weight, about 0 0.003-8000 parts by weight, about 0.003-5000 parts by weight, about 0.003-3000 parts by weight, about 0.003-1000 parts by weight, about 0.003-800 parts by weight, about 0.003-500 parts by weight Parts, about 0.003 to 300 parts by weight, about 0.003 to 100 parts by weight, about 0.003 to 10 parts by weight, about 0.005 to 100,000 parts by weight, about 0.005 to 8000 parts by weight, 005-500 0 parts by weight, about 0.005 to 3000 parts by weight, about 0.005 to 1000 parts by weight, about 0.005 to 800 parts by weight, about 0.005 to 500 parts by weight, about 0.005 to 300 parts by weight, about 0.005 to 100 parts by weight, about 0.005 to 10 parts by weight, about 0.008 to 100000 parts by weight, about 0.008 to 8000 parts by weight, about 0.008 to 5000 parts by weight, about 0.008 to 3000 Parts by weight, about 0.008 to 1000 parts by weight, about 0.008 to 800 parts by weight, about 0.008 to 500 parts by weight, about 0.008 to 300 parts by weight, about 0.008 to 100 parts by weight, about 0 0.008 to 10 parts by weight, about 0.01 to 100,000 parts by weight, about 0.01 to 8000 parts by weight, about 0.01 to 5000 parts by weight, about 0.01 to 3000 parts by weight, about 0.01 to 1000 parts by weight Parts, about 0.01-800 weight About 0.01 to 500 parts by weight, about 0.01 to 300 parts by weight, about 0.01 to 100 parts by weight, about 0.01 to 10 parts by weight, about 0.1 to 100000 parts by weight, about 0.1 -8000 parts by weight, about 0.1-5000 parts by weight, about 0.1-3000 parts by weight, about 0.1-1000 parts by weight, about 0.1-800 parts by weight, about 0.1-500 parts by weight, Examples include about 0.1 to 300 parts by weight, about 0.1 to 100 parts by weight, and about 0.1 to 10 parts by weight.

When the ophthalmic preparation is a solid preparation, the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and more preferably 0.1 mg or more. Is even more preferred. If it is the said range, while each effect of container adsorption | suction suppression of GGA and the heat | fever and light stability improvement of GGA is fully acquired, the prevention of a retinal disease, improvement, or a therapeutic effect is fully acquired.
In addition, the content of the therapeutic agent for retinal diseases other than GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less in the whole preparation. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.

  The content of the therapeutic agent for retinal diseases other than GGA in the solid preparation is 0.001 to 1000 mg, 0.001 to 100 mg, 0.001 to 10 mg, 0.01 to 1000 mg, 0.01 to 100 mg in the whole preparation. 0.01-10 mg, 0.1-1000 mg, 0.1-100 mg, 0.1-10 mg.

pH
When the ophthalmic preparation is a composition containing water, the pH is preferably 4 or more, more preferably 5.5 or more, still more preferably 6 or more, and even more preferably 6.5 or more. If it is the said range, it will become a formulation with favorable stability with respect to the heat | fever and light of GGA, and the effect of this invention will be exhibited more notably.
Moreover, 9 or less is preferable, 8.5 or less is more preferable, 8 or less is further more preferable, and 7.5 or less is further more preferable. If it is the said range, irritation | stimulation to eyes is suppressed.

Viscosity The viscosity of the ophthalmic preparation of the present invention is appropriately set according to the type and content of the ingredients, the form of preparation, the method of use, etc., as long as it is physiologically or pharmaceutically acceptable. The viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably 0.01 to 10000 mPa · s, and 0.05 to 8000 mPas. -It is more preferable that it is s, and it is still more preferable that it is 0.5-1000 mPa * s.

Combination / Combination The ophthalmic preparation of the present invention may be a one-part preparation (combination) containing GGA and a therapeutic agent for retinal diseases other than GGA in one composition, or two or more. Two or more types of preparations (combination agents) using the above composition may be used. Examples of the latter include GGA-containing ophthalmic compositions, and combined use (combination agents) of retinal disease therapeutic drug-containing ophthalmic compositions other than GGA, which have uses in combination therewith. Or the combined use (combination agent) of the retinal disease therapeutic agent containing ophthalmic composition other than GGA and the GGA containing ophthalmic composition is illustrated. In addition, it may be a combined preparation comprising a specific additive and a composition containing a specific pharmacological activity or physiologically active ingredient separately from the composition containing a therapeutic agent for retinal diseases other than GGA and GGA. In the case of a combined preparation, each composition may be filled in a separate container, or may be a ready-to-use preparation filled in a container that can be mixed at the time of use. In the case of a combined preparation, any type such as a two-drug type or a three-drug type can be adopted. One composition comprising GGA and a therapeutic agent for retinal diseases other than GGA from the standpoint of prominently exhibiting the effect of suppressing white turbidity, the effect of suppressing adsorption to containers, the effect of stabilizing heat, and / or the effect of stabilizing light of the present invention. The formulation contained therein is preferred.

  When the agent of the present invention is a combined preparation of a composition containing GGA and a composition containing other components, the GGA content described above and the content of a therapeutic agent for retinal diseases other than GGA are as follows. Is a content ratio with respect to the total amount.

Container The ophthalmic preparation of the present invention is usually contained or filled in a container (particularly an ophthalmic container). Although the kind of container is not specifically limited, For example, a plastic container, a metal container, a glass container, etc. are mentioned. Further, at least part or all of the contact surface with the preparation is made of plastic (for example, polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylterpene, fluororesin, polyvinyl chloride). , Polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, hydrocarbons optionally substituted with halogen atoms), metals (such as aluminum), and glass A container composed of at least one material selected from the above is mentioned. In addition, the container comprised with said material is 50 weight% or more per weight of container (main body), Preferably it is 60 weight% or more, More preferably, it is a ratio of 70 weight% or more. Container containing. Further, a mixture of the above materials or a copolymer may be used.

  Examples of polyolefins include polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene). And ethylene-propylene copolymer.

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

  Examples of the terephthalic acid ester include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.

  Examples of 2,6-naphthalenedicarboxylic acid esters include polyethylene naphthalate and polybutylene naphthalate.

  Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

  Examples of the polyamide include nylon.

  Examples of the polyacetal include those composed only of oxymethylene units and those partially containing oxyethylene units.

  Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.

  Examples of polyarylate include amorphous polyarylate.

  Examples of the polyimide include aromatic polyimides such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

  Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

  Examples of hydrocarbons that may be substituted with halogen atoms include hydrocarbons such as methane, ethane, propane, butane, ethylene, propylene, 1-butene, 2-butene, 1,3-butadiene; fluoromethane, difluoromethane, fluoro Form, tetrafluoromethane, 1,1-difluoroethane, 1,2-difluoroethane, 1-fluoropropane, 2-fluoropropane, 1,2-fluoropropane, 1,3-fluoropropane, 1-fluorobutane, 2- Fluorobutane, vinyl fluoride, 1,1-difluoroethylene, 1,2-difluoroethylene, trifluoroethylene, tetrafluoroethylene, 3-fluoropropene, 1,3-fluoropropene, 1,1,4,4-tetra Hydrocarbons substituted with fluorine atoms such as fluorobutadiene and perfluorobutadiene; chloromethane, dichloromethane Chloroform, tetrachloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1-chloropropane, 2-chloropropane, 1,2-chloropropane, 1,3-chloropropane, 1-chlorobutane, 2-chlorobutane, vinyl chloride, 1 1,1-dichloroethylene, 1,2-dichloroethylene, trichloroethylene, tetrachloroethylene, 3-chloropropene, 1,3-chloropropene, 1,1,4,4-tetrachlorobutadiene, perchlorobutadiene, etc. Hydrocarbons: bromomethane, dibromomethane, bromoform, tetrabromomethane, 1,1-dibromoethane, 1,2-dibromoethane, 1-bromopropane, 2-bromopropane, 1,2-bromochloropropane, 1,3- Bromopropane, 1-bromobutane, 2-bromobutane, vinyl bromide, 1,1-dibromoethylene, 1,2-dibu Hydrocarbons substituted with bromine atoms such as moethylene, tribromoethylene, tetrabromoethylene, 3-bromopropene, 1,3-bromopropene, 1,1,4,4-tetrabromobutadiene, perbromobutadiene; iodomethane, Diiodomethane, iodoform, tetraiodomethane, 1,1-diiodoethane, 1,2-diiodoethane, 1-iodopropane, 2-iodopropane, 1,2-iodopropane, 1,3-iodopropane, 1-iodobutane, 2 -Iodobutane, vinyl iodide, 1,1-diiodoethylene, 1,2-diiodoethylene, triiodoethylene, tetraiodoethylene, 3-iodopropene, 1,3-iodopropene, 1,1,4,4 -Hydrocarbons substituted with iodine atoms such as tetraiodobutadiene and periodiobutadiene are exemplified.

  Container materials are terephthalic acid ester (especially polyethylene terephthalate), polycarbonate, polymethylterpene, fluorine-substituted polyethylene (especially polytetrafluoroethylene), 2,6-naphthalenedicarboxylic acid ester (especially polyethylene naphthalate, polybutylene naphthalate). It is preferably at least one selected from the group consisting of phthalates), polyolefins (particularly polyethylene, polypropylene), and methacrylic acid esters (particularly methyl methacrylate).

  The container may have a layer or film made of the above material formed on the inner surface of the container, or the container itself may be molded of the above material. Moreover, it is sufficient that at least a part of the surface in contact with the ophthalmic preparation is composed of the above material, but it is preferable that the entire contact surface is composed of the above material.

  Further, the container may be integrally molded, or may be a container composed of two or more types of parts. In the case of a container composed of two or more parts, only one or all of the parts may be composed of the above materials, and different types of materials may be used for each part of the above materials. Good. For example, in a container having a spout or nozzle, such as an eye drop container, an eyewash container, and an eye ointment container, the entire part including the spout or nozzle may be formed of the above-mentioned material, and other than the spout or nozzle. Only the main body portion may be molded from the above material. Moreover, the layer or film comprised with the said material may be formed in the inner surface of all the parts, and the layer or film comprised with the said material may be formed only in the inner surface of the main-body part.

The shape of the container, the capacity, the thickness of the container wall, etc. are not particularly limited. Depending on the type of container, commonly used shapes, capacities, and container wall thicknesses can be employed.
For example, the capacity of the container is about 0.01 to 1000 mL, preferably about 0.1 to 500 mL, more preferably about 1 to 100 mL, and more preferably about 1 to 20 mL. Further, the thickness of the container wall is about 0.01 to 10 mm, preferably about 0.05 to 5 mm, and more preferably about 0.1 to 3 mm.
Moreover, when the layer or film which consists of said material is formed in the container inner wall, what was laminated | stacked on the main body with the shape | molded layer or film may be a layer or by vapor deposition, plasma CVD, plasma polymerization, sputtering etc. A film may be formed. The thickness of the layer or film made of the above material is not particularly limited, and can be, for example, about 10 nm to 5 mm.

Target Diseases The ophthalmic preparation of the present invention has a retinal disease such as a disease in which degeneration, damage or cell death of cells constituting the retina occurs, or a disease caused by degeneration, damage or cell death of cells constituting the retina. Can be targeted.
Examples of such diseases include glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular disease, hypertensive retinopathy, retinal vascular occlusion (retinal artery occlusion; central retinal vein occlusion, Retinal vein occlusion such as central retinal vein occlusion), retinal arteriosclerosis, retinal tear, retinal hole, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous choroidal atrophy, cerebral gyrus Reticulochoroidal atrophy, Colloideremia, Crystalline retinopathy, White spotted retinopathy, Cone dystrophy, Central crested choroidal dystrophy, Dinbee's nest retinal dystrophy, Yolk macular dystrophy, Cystic tissue macular edema, Occult macular dystrophy, Stargardt disease, retinal sequestration, central serous chorioretinopathy (central retinopathy), spinocerebellar degeneration type 7, familial exudative vitreoretinopathy, Examples include cone enhancement syndrome, retinal pigment streaks, autosomal dominant optic atrophy, autosomal dominant drusen, familial drusen, acute occult retinal retinal disease, cancer-related retinopathy, photodamage, and ischemic retinopathy .
Among them, glaucoma, retinal pigment degeneration, age-related macular degeneration, and diabetic retinopathy are suitable target diseases, and glaucoma is a more preferable target disease.

In addition, the ophthalmic preparation of the present invention can be used for diseases in which any cell constituting the retina is damaged, or diseases caused by damage to any cell constituting the retina. Examples of retinal constituent cells include retinal ganglion cells, amacrine cells, horizontal cells, Müller glial cells, bipolar cells, retinal photoreceptor cells (cones and rods), and retinal pigment epithelial cells. In particular, a disorder in which retinal ganglion cells or retinal pigment epithelial cells are damaged or caused by the damage of these cells is preferred.
Further, the preparation of the present invention comprises the layers constituting the retina, that is, the inner boundary membrane, nerve fiber layer, ganglion cell layer, inner reticular membrane, inner granule layer, outer reticular layer, outer granule layer, outer boundary membrane, visual A disease in which any of the cell layer and the retinal pigment epithelium layer is damaged, or a disease caused by a failure in any of these layers can be targeted. In particular, disorder of the ganglion cell layer, inner granule layer, or outer granule layer is a suitable subject.
The target disease may be one type or two or more types.

  Therefore, the ophthalmic preparation of the present invention can be used for the prevention, amelioration, or treatment of retinal diseases, the prevention of retinal cell degeneration, damage, or cell death, or the protection of retinal cells. In addition, as shown in the item of the examples, since GGA has an action of inducing neurite outgrowth of cells such as the retina, (retinal) neurite outgrowth promotion or induction, (retinal) cell function improvement, or A preparation for improving or improving the survival state of retinal cells can also be used.

  In the present invention, “prevention” includes avoidance, delay, or reduction in the incidence of onset, and “improvement” and “treatment” include amelioration of symptoms, suppression of progression of symptoms, and cure or completeness. .

Method of Use When the preparation of the present invention is an eye drop, the eye drop containing GGA at the above-mentioned concentration is, for example, about 1 to 5 drops, preferably about 1 to 3 drops, more preferably about 1 to 2 drops. Drops may be instilled about 1 to 7 times, preferably about 1 to 5 times, more preferably about 1 to 3 times a day.
When the preparation of the present invention is an eye wash, the eye wash containing GGA at the above concentration is used, for example, about 1 to 20 mL per time, about 1 to 10 times a day, preferably about 1 to 5 times a day. Wash your eyes once.
When the preparation of the present invention is an eye ointment, an eye ointment containing GGA at the above concentration is, for example, about 0.001 to 5 g per time, about 1 to 7 times a day, preferably 1 to 1 day a day. It may be applied to the eye 5 times, more preferably about 1 to 3 times.
When the preparation of the present invention is an intraocular injection, the injection containing GGA at the above concentration is about 0.005 to 1 mL per time, about 1 to 3 times per day, preferably 1 to 3. What is necessary is to inject once.
In addition, when the preparation of the present invention is a contact lens solution (cleaning solution, preservative solution, disinfectant solution, multipurpose solution, package solution), a preservative for isolated eye tissue such as a cornea for transplantation, or a perfusate during surgery Compositions containing GGA at the above concentrations may be used at the usual dosage of these formulations.
Further, when the preparation 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 one, for example, about 1 to 3 times, preferably once every 1 to 14 days. That's fine.
In addition, when the preparation of the present invention is a sustained-release intraocular implant, it may not be replaced with a new implant, but may be replaced with a new implant containing the above amount of GGA. In this case, for example, it may be replaced once every about 1 day to 10 years. For example, some implants have a relatively long period of time for replacement, such as implants for the posterior segment of the eye, but others may be replaced with a new implant once every about 1 to 14 days.

In any dosage form, the daily dosage of GGA when the ophthalmic preparation of the present invention is used is preferably 50 ng or more, more preferably 500 ng or more, and even more preferably 5 μg or more. The daily dose of GGA is preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.
Daily dosages of GGA include 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 are mentioned.

In any dosage form, the daily dose of the component (b) (the remedy for retinal diseases other than GGA) when using the ophthalmic preparation of the present invention is preferably 50 ng or more, more preferably 500 ng or more. Preferably, 5 μg or more is even more preferable. The daily dose of component (b) is preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.
The daily dose of component (b) includes 50 ng to 50 mg, 500 ng to 50 mg, 5 μg to 50 mg, 50 ng to 20 mg, 500 ng to 20 mg, 5 μg to 20 mg, 50 ng to 10 mg, 500 ng to 10 mg, 500 ng to 10 mg, 5 μg to 10 mg. .

  The ophthalmic preparation of the present invention is administered to the eye, and the administration method varies depending on the kind of the preparation, and includes eye drop, eye wash, application to the eye, spray on the eye, implantation in the eye, wearing of a contact lens, glass Examples include injection into the eye such as the body.

  When the ophthalmic preparation of the present invention is a combination preparation separately comprising a composition containing GGA and a composition containing component (b), the composition containing GGA and the composition containing component (b) are simultaneously used. For example, any one of the composition containing GGA and the composition containing component (b) may be administered later at intervals of 12 hours, 6 hours, or 2 hours. . When the interval is set, any of these may be administered first. However, it is more effective to administer the composition containing GGA and then administer the composition containing component (b). Hyperemia can be suppressed.

In addition, the present invention allows (a) GGA and (b) retinal disease therapeutic agent (excluding GGA) to coexist in an ophthalmic composition, thereby (b) retinal disease therapeutic agent (provided that GGA). And the method for imparting an action to suppress conjunctival hyperemia and / or corneal injury to the ophthalmic composition. In other words, this method comprises (a) GGA and (b) a retinal disease therapeutic agent (excluding GGA) in the ophthalmic composition, thereby (b) a retinal disease therapeutic agent ( However, it is a method of reducing the side effects of conjunctival hyperemia and / or corneal injury that GGA) (excluding GGA) has.
From the coexistence of (a) GGA and (b) retinal disease therapeutic agent (excluding GGA), the above side effects of (b) retinal disease therapeutic agent (excluding GGA) are suppressed or reduced. However, it is preferable to coexist for 1 day or more, 3 days or more, or 1 week or more. The coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and particularly 1 to 30 ° C. The coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.

The present invention also provides a method for suppressing white turbidity of an ophthalmic composition by allowing (a) GGA and (b) a retinal disease therapeutic agent (excluding GGA) to coexist in the ophthalmic composition. Is included.
The cloudiness of the ophthalmic composition containing GGA is likely to occur particularly when the GGA concentration in the ophthalmic composition is high. According to the method of the present invention, even when the GGA concentration is 0.01% by weight or more, particularly 0.03% by weight or more, particularly 0.05% by weight or more, particularly 0.08% by weight or more, and particularly 0.1% by weight or more, white turbidity is caused. Can be suppressed. Further, normally, white turbidity is suppressed at a GGA concentration of 10% by weight or less. Also, coexistence, that is, (b) combination of a therapeutic agent for retinal diseases (excluding GGA) into an ophthalmic composition containing GGA, or ( b) The composition of GGA into the ophthalmic composition containing a retinal disease therapeutic agent (excluding GGA) may be carried out at a temperature of about 1 to 80 ° C, particularly about 1 to 70 ° C. Further, in the method of the present invention, the cloudiness of the ophthalmic composition at a low temperature is also suppressed. The “low temperature” can be, for example, 10 ° C. or less, particularly 6 ° C. or less, especially 4 ° C. or less. The lower limit of “low temperature” may be a temperature at which the composition does not freeze, but may be, for example, −10 ° C. or higher, particularly −5 ° C. or higher, and especially 0 ° C. or higher.
The coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.

The present invention relates to a container for GGA (particularly, an ophthalmic container) by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in an ophthalmic composition. Includes adsorption suppression methods. In other words, this method adsorbs to an ophthalmic container of GGA by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in the ophthalmic composition. This is a method for suppressing the property.
The type of the container (in particular, the ophthalmic container) is as described for the ophthalmic preparation of the present invention.
Although (a) GGA and (b) retinal disease therapeutic agent (excluding GGA) coexist, adsorption of GGA to the container is suppressed, but preferably 1 day or more, 3 days or more Or coexist for one week or longer. The coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and particularly about 1 to 30 ° C. The coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.

The present invention improves the stability of GGA to heat and / or light by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in an ophthalmic composition. The method of making it.
Although the stability of GGA to heat and / or light is improved from the coexistence of (a) GGA and (b) retinal disease therapeutic agent (excluding GGA), What is necessary is just to coexist for 3 days or more, or 1 week or more.
In the present invention, improvement in heat stability was confirmed by increasing the residual ratio of GGA when the ophthalmic composition was allowed to stand at 40 ° C. for 7 days. Specifically, the method described in Examples Confirm with Further, the improvement in the stability to light was confirmed by an increase in the residual ratio of GGA when the ophthalmic composition was irradiated with 1.3 million lx · h of light, and specifically described in the examples. Check by method.
The coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and particularly about 1 to 30 ° C. The coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding. The prepared ophthalmic composition is usually stored at a temperature of about 1 to 30 ° C., but during the preparation of the ophthalmic composition, a temperature of about 1 ° C. or more and about 70 ° C. or less or about 80 ° C. or less. May be placed underneath.

In each method of the present invention, the ophthalmic composition being prepared also corresponds to the ophthalmic composition. That is, each method of the present invention corresponds to “coexistence” from the time when (a) GGA and (b) component are both present in the composition to be an ophthalmic composition.
In each method of the present invention, whether or not an ophthalmic composition containing (a) GGA and component (b) or an ophthalmic composition being prepared is contained in a container (particularly an ophthalmic container) is used. If (a) GGA and (b) component are contained in the ophthalmic composition or the ophthalmic composition being prepared, it falls under “coexistence of (a) GGA and (b) component”. .

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples. In the following examples, the content of the component may be expressed in w / v%. However, if the composition of each of these samples is taken into consideration, the component content expressed in w / v% is weight%. It becomes substantially the same value as the component content indicated by.
Note that the containers used in the following tests have a thickness of about 0.5 to 1.5 mm.

(1) Preparation of geranylgeranylacetone A commercially available teprenone (all-trans isomer: 5Z monocis isomer = weight ratio 3: 2) (Wako Pure Chemical Industries, Ltd.) was obtained, and the all-trans isomer was purified by silica gel chromatography.
As specific conditions, silica gel (PSQ60B manufactured by Fuji Silysia Chemical Co., Ltd.) was filled in a glass tube, and preparative purification was performed using a mobile phase (n-hexane: ethyl acetate = 9: 1). After fractionation, each fraction was concentrated and dried under reduced pressure, and the purity and structure of the all-trans isomer were confirmed by GC and 1H-NMR (solvent: deuterated chloroform, internal standard: tetramethylsilane), respectively (yield approximately 20%).
A 5Z monocis was also purified from commercially available teprenone by the same method as described above.

<GC measurement conditions>
Column: DB-1 (J & W scientific, 0.53 mm × 30 m, film thickness 1.5 μm)
Column temperature: 200 ° C. → 5 ° C./min→300° C. (10 minutes)
Vaporization chamber temperature: 280 ° C
Detector temperature: 280 ° C
Carrier gas: Helium Hydrogen pressure: 60 kPa
Air pressure: 50kPa
Makeup gas pressure: 75 kPa (nitrogen gas)
Total flow rate: 41 mL / min
Column flow rate: 6.52 mL / min
Linear velocity: 58.3 cm / sec
Split ratio: 5: 1
Injection volume: 0.1 μL of 0.1 g / 100 mL (ethanol solution) sample

  Commercially available teprenone and the all-trans isomer purified as described above were mixed in an arbitrary ratio to prepare an all-trans: 5Z monocis (weight ratio) = 8: 2 GGA. Further, by mixing with the 5Z monocis purified as described above, an all-trans: 5Z monocis (weight ratio) = 2: 8 GGA was prepared. Since stability by mixing was not confirmed, it was prepared at the time of use.

(2) Evaluation of protective effect of retinal neurons from hypoxia / glucose-induced ischemia-like cell death
The progression of visual field impairment in glaucoma involves the death of optic ganglion cells (RGC) due to blood flow failure near the optic nerve (Folia Pharmacol. Jpn. 128, 255-258 (2006)). A representative neuronal cell line established from rat adrenal medulla chromaffin cell tumor and used as a model cell for the evaluation of RGC function (J Neurosci Res. 2000 May 15; 60 (4): 495-503. ) PC12 was used to test the cytoprotective effect of GGA from hypoxia and glucose-induced ischemia-like cell death.

(Evaluation method)
The test substance was prepared as follows. That is, the test substances were four types of GGA containing all-trans isomers and 5Z monocis isomers in weight ratios of 10: 0, 8: 2, 6: 4, and 0:10. 100 mg of each GGA, 0.25 mg of DL-α-tocopherol acetate (Wako Pure Chemical Industries) as an antioxidant was weighed, dissolved in 789 mg of 100% ethanol, and prepared in the same manner except that it did not contain GGA As a base. The 10: 0, 8: 2 and 6: 4 GGA dissolved in 789 mg of 100% ethanol are 10% (v / v) horse serum (DS Pharma Biomedical), 5% (v / v) fetal bovine serum ( Diluted at a concentration corrected to include substantially 30 μM of all-trans form in Dulbecco's modified Eagle basal medium (DMEM) with a high glucose concentration (4.5 g / L) supplemented with Daiichi Kagaku) The 0:10 GGA containing only was diluted to 30 μM. The base was diluted at the same dilution ratio as that for preparing GGA having a weight ratio of 6: 4 between the all-trans isomer and the 5Z monocis isomer.

PC12 (obtained from DS Pharma Biomedical) was seeded on a collagen IV-coated 96-well microplate (IWAKI) at 100 × L to 2.0 × 10 ⁴ cells per well, and the above DMEM was used at 37 ° C. The cells were cultured for 48 hours under conditions of 5% CO ₂ .

After 48 hours of culturing, the cell culture supernatant was removed, replaced with the previously prepared DMEM containing GGA, and cultured for 2 hours at 37 ° C. and 5% CO ₂ . After 2 hours of culture, the medium was replaced with DMEM with a low glucose concentration (1.0 g / L) supplemented with 2% horse serum and 1% fetal bovine serum, and aneropack 5% (37 ° C., 5% CO ₂ , hypoxia conditions) (Mitsubishi Gas Chemical) was used to change to 0% O ₂ and cultured for 8 hours. 2% (v / v) horse serum, 1% (v / v) fetal bovine serum with high glucose concentration (4.5 g / L) DMEM, 37 ° C., 5% CO ₂ , normal oxygen concentration The uncultivated group was cultured for 8 hours below.

(Test results)
Eight hours after culturing, 100 μL of a mixture of the same amount of live cell detection reagent Cell Titer-Glo (Promega) and PBS was added to each well, and the amount of luminescence generated by reaction with live ATP was determined by luminosity. Measurement was performed with a meter (GloMax; manufactured by Promega). The cell protection effect by GGA from oxidative stress caused by hydrogen peroxide was evaluated by calculating the cell viability with the following formula based on the measured amount of luminescence.

Cell viability (%)
= [(Luminous amount of base or GGA treatment group) / (Luminous amount of untreated group)] × 100

  The results are shown in FIG. The GGA treatment group showed significantly higher cell viability than the base treatment group at any weight ratio (n = 10, * P <0.05, ** P <0.01, Tukey-kramer test). by).

(3) Evaluation of neurite outgrowth-inducing effect using rat-derived retinal ganglion cell (RGC) culture system The progression of visual field impairment in glaucoma involves the death of optic ganglion cells (RGC) due to blood flow failure near the optic nerve. (Folia Pharmacol. Jpn. 128, 255-258 (2006)). Therefore, GGA neurite outgrowth using a rat-derived retinal nerve culture system (Current protocols in Neuroscience 3.22. 1-3.22.10, October 2010) is widely used as one of the tools for studying optic nerve diseases such as glaucoma. The inductive effect was tested.

(Evaluation method)
Four-day-old Wistar rats (Japan SLC Co., Ltd.) were euthanized by cervical dislocation and the eyeballs were removed. The extracted eyeball was immersed in 70% ethanol for 10 seconds, then transferred to Hanks balanced salt solution containing 100 U / mL penicillin and 100 μg / mL streptomycin, and using a surgical scissors and scissors under a stereomicroscope, the cornea, iris, The lens and vitreous were removed and the retinal tissue was removed. The extracted retinal tissue was treated with 100 U / mL penicillin, 100 μg / mL streptomycin, nerve cell culture additives (B27 ^™ -Supplement, manufactured by Invitrogen), 1 μM L-cysteine (Kyowa Hakko Bio) and 15 U / mL papain ( It was transferred to a centrifuge tube containing 5 mL of a basal medium (Neurobasal, manufactured by Invitrogen) containing neuronal cell culture containing Sigma Aldrich and incubated at 37 ° C. for 30 minutes. After 30 minutes, the supernatant was removed and washed twice with Neurobasal containing 100 U / mL penicillin, 100 μg / mL streptomycin and B27 ^™ -Supplement. After washing, 2 mL of Neurobasal was added, and the tissue was made into a small cell mass by pipetting with a dry heat sterilized Pasteur pipette (Hirgenberg) and transferred to 50 mL of Neurobasal prepared in advance. After centrifuging at 900 × g for 5 minutes to remove the supernatant, the suspension was again suspended with 6 mL of Neurobasal to prepare a cell suspension. The cell suspension was passed through a 40 μm nylon mesh cell strainer (Japan BD) to remove the aggregated cell mass, and then the cells were seeded on a poly-D-lysine / laminin-coated 6-well plate (Japan BD). ° C., and cultured in a 5% CO ₂ condition.

The test substances were 5 G mono isomers, and two types of GGA of a mixture containing all-trans isomers and 5 Z mono cis isomers in a weight ratio of 2: 8. 100 mg of each GGA, 0.25 mg of DL-α-tocopherol acetate (Wako Pure Chemical Industries) as an antioxidant was weighed, dissolved in 789 mg of 100% ethanol, and prepared in the same manner except that it did not contain GGA A base was used. GGA mixture of 5Z monocis: all-trans isomer weight ratio of 0:10 (5Z monocis) and 2: 8 GGA dissolved in 789 mg of 100% ethanol will contain substantially 3 μM of 5Z monocis. And the base was added to the cell culture supernatant 2 hours after cell seeding so that the dilution ratio was the same as when preparing 6: 4 GGA, and the conditions were 37 ° C. and 5% CO ₂ . Cultured for 48 hours.

(result)
After 48 hours of culture, the cell culture supernatant was removed, and the cells were fixed with 4% paraformaldehyde / phosphate buffer (Wako Pure Chemical Industries) and 100% methanol (Wako Pure Chemical Industries) at room temperature for 30 minutes. After washing the cells with phosphate buffer (PBS, manufactured by Kojin Bio Inc.), PBS containing 2% (w / v) bovine serum albumin (Sigma Aldrich) and 0.05% (v / v) Tween 20 (Sigma Aldrich) was used. And blocked for 30 minutes at room temperature. After 30 minutes, a 1000-fold diluted solution of βIII tubulin antibody (Promega) was prepared in PBS, 1 mL was added to each well, and incubated at room temperature for 2 hours. After 2 hours, the antibody diluted solution was removed and washed 3 times with PBS, and then a 1000-fold dilution of Alexa Fluor 488 Goat Anti-mouse antibody (Invitrogen) was prepared in PBS. And incubated for 1 hour. After 1 hour, the antibody diluted solution was removed, washed 3 times with PBS, 3 mL of PBS was added to each well, and each of them was measured with an imaging cytometer (In Cell Analyzer 1000, manufactured by GE Healthcare Bioscience). Arbitrary four points of the well were observed (excitation wavelength: 475 nm, fluorescence wavelength: 535 nm), and the average value of the length (μm) of the fluorescence-stained RGC neurites was calculated.

  The results are shown in FIG. Each GGA treatment group in which the weight ratio of the all-trans isomer to the 5Z monocis isomer was 0:10 and 2: 8 showed a stronger neurite inducing action than the base treatment group.

(4) Evaluation of suppression of hyperemia
GTA-containing eye drops (compositions are shown in Table 1) were instilled into 30 μL of only one eye on 6 rabbits (Japanese white species) combined with latanoprost and GGA . As GGA, one containing an all-trans isomer and a 5Z monocis isomer at a weight ratio of 10: 0 was used. Furthermore, eye drops containing 0.005 w / v% latanoprost (product name: xalatan ophthalmic solution 0.005%, Pfizer Inc.) were instilled into both eyes at 30 μL. Four hours after the instillation, the conjunctiva of the upper eyelid of the rabbit was inverted, and the degree of hyperemia observed within 30 seconds was scored according to the criteria in Table 2. Tests under blinded conditions were performed by a separate investigator in charge of eye drops and evaluation of hyperemia.

The results are shown in FIG. Conjunctival hyperemia, which is a side effect of latanoprost, was clearly suppressed by using GGA in combination with latanoprost, which is a prostaglandin drug.

30 μL of GGA-containing eye drops were applied to only one eye on 6 rabbits (Japanese white species) combined with fasudil hydrochloride and GGA . As GGA, one containing an all-trans isomer and a 5Z monocis isomer at a weight ratio of 10: 0 was used. Two hours later, 0.02 w / v% solution of fasudil hydrochloride (Wako Pure Chemical Industries) dissolved in PBS was instilled into both eyes of rabbits by 30 μL. Four hours later, the conjunctiva of the upper eyelid of the rabbit was inverted, and the degree of hyperemia observed within 30 seconds was scored according to the criteria in Table 1 above. Tests under blinded conditions were performed by a separate investigator in charge of eye drops and evaluation of hyperemia.
The results are shown in FIG. Conjunctival hyperemia, which is a side effect of fasudil hydrochloride, was clearly suppressed by using GGA in combination with fasudil hydrochloride, which is a ROCK inhibitor.

(5) Evaluation of suppression of cytotoxicity
As the test method GGA, GGA having a weight ratio of 10: 0 to the all-trans isomer and the 5Z monocis isomer was used. 100 mg of GGA and 0.25 mg of α-tocopherol (Wako Pure Chemical Industries) as an antioxidant were weighed and dissolved in 789 mg of 100% ethanol. GGA dissolved in ethanol was diluted and dissolved in Dulbecco's modified Eagle basal medium / Ham F12 equimixed liquid medium (DMEM / F-12, manufactured by Invitrogen) to a final concentration of 300 μM. A base prepared in the same manner except that it did not contain GGA was used.

Human corneal epithelial cells (HCET) are seeded in a 96-well microplate (CORNING) so as to be 3.0 × 10 ⁴ cells per well, 0.5% DMSO (Wako Pure Chemical Industries), 10 ng / Dulbecco's Modified Eagle Basal Medium / Ham F12 equimixed liquid supplemented with mL epidermal growth nutrient factor (R & D), 5 μg / mL insulin (Invitrogen), and 5% (v / v) fetal calf serum (first chemical) Culture was performed in a medium (DMEM / F-12, manufactured by Invitrogen) at 37 ° C. and 5% CO ₂ .
After 24 hours of culturing, an eye drop containing 0.5 w / v% timolol maleate (product name: timoptol eye drop 0.5% (Santen Pharmaceutical)) or an eye drop containing 1 w / v% dorzolamide hydrochloride ( (Product name: Torsopt ophthalmic solution 1%, MSD Co., Ltd.) was diluted and added so that the final concentration in the culture supernatant was 1%. At the same time, the above GGA solution or base was added so that the final concentration in the culture supernatant was 3 to 30 μM, and further cultured.
After 48 hours of culture, the cell culture supernatant was removed, 200 μL of PBS was added, and PBS was immediately removed. 100 μL of a mixture of an equal amount of a living cell detection reagent Cell Titer-Glo (Promega) and PBS was added to each well, and the amount of luminescence generated by reaction with ATP in living cells was measured using a luminometer (GloMax; Promega). Manufactured). The protective effect by GGA from the cytotoxicity of glaucoma eye drops was evaluated based on the cell viability calculated according to the following formula based on the measured amount of luminescence.

Cell viability (%)
= [(Luminous amount of base or GGA treatment group) / (Luminous amount of untreated group)] × 100

The result is shown in FIG. Timolol maleate, a β-blocker, or dorzolamide hydrochloride, a carbonic anhydrase inhibitor, decreased cell viability of human corneal epithelial cells and was cytotoxic. By using GGA in combination with timolol maleate or dorzolamide hydrochloride, cytotoxicity of timolol maleate and dorzolamide hydrochloride was clearly suppressed. Since corneal epithelial damage is known to lead to eye irritation, GGA is also expected to suppress eye irritation upon instillation of β-blockers and carbonic anhydrase inhibitors.

(6) Evaluation of suppression of cloudiness of composition To surfactants (polysorbate 80 and POE castor oil) heated to 65 ° C., teprenone (Wako Pure Chemical Industries, Ltd.), teprenone and latanoprost, or teprenone and timolol maleate The mixture was stirred and dissolved in a 65 ° C. hot water bath for 2 minutes, 65 ° C. water was further added, and the mixture was mixed and stirred to obtain a uniform solution. This solution was filtered through a membrane filter having a pore size of 0.2 μm (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to prepare a clear eye drop having the composition shown in Table 3.

  These eye drops were dispensed into 96-well plates (flat bottom, made of polystyrene) by 0.2 mL each using a glass measuring pipette, and 660 nm (inside apparatus temperature of 20 to 20) using a microplate reader device (VersaMax manufactured by Molecular Devices). The absorbance at 25 ° C. was measured. With reference to JIS K0101 (industrial water test method, transmitted light turbidity measurement), the absorbance at 660 nm of each sample was used as an index of turbidity (turbidity).

By using GGA in combination with a prostaglandin drug or β-blocker, the turbidity of the GGA-containing composition was reduced, and white turbidity was suppressed.

(7) Evaluation of inhibition of adsorption of GGA onto container Containers containing teprenone (Wako Pure Chemicals), teprenone and latanoprost, teprenone and timolol maleate, and teprenone and fasudil hydrochloride were prepared as follows. Prepared. Tables 4 and 5 show the composition of each eye drop.
Specifically, a surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C. is charged with teprenone, teprenone and latanoprost, teprenone and timolol maleate, or teprenone and fasudil hydrochloride, and heated at 65 ° C. After stirring and dissolving in a bath for 2 minutes and adding water at 65 ° C., each buffer solution was mixed and stirred to obtain a homogeneous solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide. This solution was filtered through a membrane filter having a pore size of 0.2 μm (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop.
In each operation, a sterile eye drop was prepared after confirming in advance by HPLC described later that the content of GGA was not reduced by adsorbing to an instrument or the like.

  Each eye drop was dispensed in a 15 mL capacity plastic container by 5 mL with a glass whole pipette and sealed. The container material and capacity will be described in Table 6 below. A stability test was carried out in 8 hours at 40 ° C. and 75% RH in a state where these were left standing upright in a test tube stand. Under the above-mentioned HPLC conditions, immediately after production and after standing for 8 hours, teprenone (g / 100 mL) in each eye drop was quantified to calculate a GGA residual ratio (%).

The GGA concentration in the preparation was measured as follows.
GGA concentration confirmation method Japanese Pharmacopoeia “Teprenone standard (all-trans: 5Z monocis = weight ratio approx. 6: 4, manufactured by Pharmaceuticals and Medical Devices Regulatory Science Foundation)” or Teprenone (Wako Pure Chemical Industries) As a standard product, the area value (Ac) of 5Z monocis was measured under the following HPLC measurement conditions in accordance with the measurement conditions of the dissolution test described in “No. 41002007 Teprenone 100 mg / g fine granules” from the Pharmaceutical Diet Examination. The concentration of GGA contained in each eye drop was measured from the area value (At) of the all-trans form. For teprenone (all-trans isomer: 5Z monocis isomer = weight ratio 3: 2), the total amount of all-trans isomer and 5Z monocis isomer was calculated as the GGA content.

<HPLC measurement conditions>
Detector: UV absorption photometer (measurement wavelength: 210 nm)
Column: YMC-Pack ODS-A (inner diameter 4.6 mm, length 15 cm, particle size 3 μm)
Column temperature: 30 ° C
Mobile phase: 90% acetonitrile solution Flow rate: 1.2 to 1.3 mL / min (eluted in the order of 5Z monocis and all-trans)
Injection amount: 5 μL injection of 0.05 g / 100 mL sample

GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic β-blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved.
Since there is a difference in the content of GGA between polystyrene containers containing eye drops and polypropylene containers, the mixing of latanoprost, timolol maleate, or fasudil hydrochloride suppressed the adsorption of GGA to the container wall. I understand.

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

(8) Evaluation of thermal stability of GGA Eye drops containing teprenone, latanoprost, timolol maleate, and fasudil hydrochloride were prepared as follows. Table 7 shows the composition of each eye drop.
Specifically, teprenone, latanoprost, timolol maleate, or fasudil hydrochloride is added to a surfactant (polysorbate 80 and POE castor oil) heated to 65 ° C. for 2 minutes in a 65 ° C. hot water bath. After stirring and dissolving, and further adding water at 65 ° C., each buffer solution was mixed and stirred to obtain a uniform solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide. This solution was filtered through a membrane filter having a pore size of 0.2 μm (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. It should be noted that in each operation, teprenone is adsorbed to a device or the like, and the content does not decrease. After confirming in advance by HPLC described in the item of “(7) Evaluation of inhibition of adsorption of GGA to container”, aseptic eye drops An agent was prepared.
A 10 mL capacity transparent glass container (manufactured by Nippon Denka Glass) was aseptically filled. These eye drops were subjected to a stability test at 40 ° C. and 75% RH for 7 days with the container upright. Under the above HPLC conditions, the teprenone content (g / 100 mL) in the eye drop was quantified immediately after production and after standing for 7 days, and the residual rate (%) was calculated.

  GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic β-blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved. It turns out that the stability with respect to the heat | fever of GGA improved by the combination of latanoprost, timolol maleate, and fasudil hydrochloride.

(9) Evaluation of photostability of GGA Eye drops each containing teprenone, latanoprost, timolol maleate, and fasudil hydrochloride were prepared as follows. Table 8 shows the composition of each eye drop.
Specifically, teprenone, timolol maleate, or fasudil hydrochloride is added to a surfactant heated to 65 ° C. (polysorbate 80 and POE castor oil), and stirred and dissolved in a 65 ° C. water bath for 2 minutes. After adding 65 ° C. water, each buffer solution was mixed and stirred to obtain a homogeneous solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide. This solution was filtered through a membrane filter having a pore size of 0.2 μm (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. In each operation, a sterile eye drop was prepared after confirming in advance by HPLC described later that the content of GGA was not reduced by adsorbing to an instrument or the like.

The prepared eye drop was aseptically filled into a polyethylene terephthalate container (Rohto Pharmaceutical, ROH Dry Aid EX container; capacity of about 8 mL). Each eye drop was irradiated with light under the following conditions, the teprenone content in the sample immediately after production and after irradiation was quantified, and the residual rate (%) was calculated.
Irradiation device: LTL-200A-15WCD (manufactured by Nagano Science)
Light source: D-65 lamp Total irradiation amount: 1.3 million lx · h (4000 lx × 325 hours)
Temperature and humidity: 25 ° C 60% RH
Light irradiation direction: Irradiation from above with the container upright on the internal rotating disk

GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic β-blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved. It can be seen that the light stability of GGA was improved by blending latanoprost, timolol maleate, and fasudil hydrochloride.

The ophthalmic preparation of the present invention is excellent in the effect of preventing, improving, or treating retinal diseases, and is safe for a long time because conjunctival hyperemia and / or corneal disorders, which are side effects of drugs for treating retinal diseases other than GGA, are suppressed. It is a useful preparation that can be used in
Further, the ophthalmic preparation of the present invention has advantageous properties as an ophthalmic preparation, such as excellent clarity, suppression of GGA adsorption to a container, and excellent GGA light stability. It is useful for.

Claims (19)

  An ophthalmic preparation comprising (a) geranylgeranylacetone and (b) a retinal disease therapeutic agent (excluding geranylgeranylacetone).   Retinal diseases (excluding geranylgeranylacetone) are prostaglandins, sympathetic blockers, sympathomimetics, parasympathomimetics, carbonic anhydrase inhibitors, ROCK inhibitors, calcium antagonists, EP2 The ophthalmic preparation according to claim 1, which is at least one member selected from the group consisting of an agonist, an adenosine A2a receptor agonist, a VEGF aptamer, and a VEGF inhibitor.   The ophthalmic preparation according to claim 1, which is used for prevention, improvement or treatment of retinal diseases.   Retinal diseases are glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular disease, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tear, retinal hole, macular Hole, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous choroidal atrophy, gyrus reticulochoroidal atrophy, choroideremia, crystal retinopathy, white spot retinopathy, pyramidal dystrophy, central cricoid choroidal dystrophy, Doinbee's focal retinal dystrophy, yolk macular dystrophy, cystic macular edema, occult macular dystrophy, Stargardt's disease, retinoschisis, central serous chorioretinopathy, spinocerebellar degeneration type 7, familial exudative Vitreoretinopathy, S cone augmentation syndrome, retinal pigment streak, autosomal dominant optic atrophy, autosomal dominant drusen, acute occult retinal outer layer disease, cancer-related Endometriosis, ophthalmic preparation according to claim 3 photodamage, and is one or more diseases selected from the group consisting of ischemic retinopathy.   Eye drops, intraocular injections, eye ointments, eye washes, contact lens mounting fluids, contact lens fluids, cornea-extracted eye tissue preservatives for transplantation, surgical perfusion fluids, sustained-release intraocular implants, The ophthalmic preparation according to claim 1, which is a sustained-release contact lens preparation.   The ophthalmic preparation according to claim 1, which is an aqueous composition or an oily composition.   The ophthalmic preparation according to claim 1, which is liquid, fluid, gel, or semi-solid.   The ophthalmic preparation according to claim 1, wherein the property of congesting the conjunctiva and / or the property of damaging the cornea of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) is suppressed.   The ophthalmic preparation according to claim 1, wherein adsorption of geranylgeranylacetone to the container is suppressed.   The ophthalmic preparation according to claim 1, wherein white turbidity is suppressed.   The ophthalmic preparation according to claim 1, wherein the stability of geranylgeranylacetone to heat and / or light is improved.   The ophthalmic preparation according to claim 1, comprising geranylgeranylacetone in an amount of 0.00001 to 90% by weight based on the total amount of the preparation.   The ophthalmic preparation according to claim 1, comprising 0.00001 to 90% by weight of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) with respect to the total amount of the preparation.   The ophthalmic preparation according to claim 1, comprising 0.0001 to 100,000 parts by weight of a retinal disease therapeutic drug (excluding geranylgeranylacetone) with respect to 1 part by weight of geranylgeranylacetone.   The geranylgeranylacetone and a retinal disease therapeutic drug (excluding geranylgeranylacetone), which are included in the same composition, or a combined preparation containing geranylgeranylacetone in separate compositions. Ophthalmic formulation.   By coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition, (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) ) To suppress the conjunctival hyperemia and / or corneal injury to the ophthalmic composition.   A method for suppressing white turbidity of an ophthalmic composition by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in the ophthalmic composition.   A method for suppressing adsorption of geranylgeranylacetone to a container by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in an ophthalmic composition.   Improve heat and / or light stability of geranylgeranylacetone by coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition. Method.