NZ715245B2

NZ715245B2 - Inhibitor for retinochoroidal disorders

Info

Publication number: NZ715245B2
Application number: NZ715245A
Authority: NZ
Inventors: Kazuhiro Kimura
Original assignee: Yamaguchi University
Priority date: 2013-05-22
Filing date: 2014-05-21
Publication date: 2021-08-03

Abstract

The present invention addresses the problem of providing an inhibitor for retinochoroidal disorders, in particular, an inhibitor for retinochoroidal scar formation and retinochoroidal atrophy in an epiretinal, intraretinal or subretinal tissue. This problem can be solved by preparing an inhibitor for retinochoroidal disorders which comprises, as an active ingredient, (E)-4-(2-{3-[(1H-pyrazol-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl}vinyl)benzoic acid, an ester thereof or a salt of the same. The inhibitor for retinochoroidal disorders can inhibit collagen atrophy of retinal pigment epithelium cells, fibroblasts, glial cells and the like and thus inhibit retinochoroidal disorders. r retinochoroidal disorders which comprises, as an active ingredient, (E)-4-(2-{3-[(1H-pyrazol-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl}vinyl)benzoic acid, an ester thereof or a salt of the same. The inhibitor for retinochoroidal disorders can inhibit collagen atrophy of retinal pigment epithelium cells, fibroblasts, glial cells and the like and thus inhibit retinochoroidal disorders.

Description

[DESCRIPTION] [Title of Invention] INHIBITOR FOR RETINOCHOROIDAL DISORDERS [Technical Field] The t disclosure relates to an inhibitor of retinochoroidal disorder comprising (E)(2-{3-[(1H-pyrazolyl)methyl]-5,5,8,8-tetramethyl-5 ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid, an ester thereof or a salt thereof as an effective ingredient.

[Background Art] In Japan where the society has an aging population, the ratio of vitreoretinal diseases such as diabetic retinopathy, retinal detachment, and age-related macular degeneration is expected to continue to increase as a cause of blindness. sis of such diseases, which ed in blindness in the past, is improving by the development of vitreoretinal operation and introduction of biopharmaceuticals, such as anti-VERF intraocular injections. However, aside from initial symptoms, the prognosis of visual functions in severe cases, where symptoms were left untreated for a long period of time or are ing, is still not ble. Even if retinopexy is attained by an operation or intraocular neovascularity can be devised to disappear with a pharmaceutical agent, photoreceptor functions would decrease if retinal cells have already suffered an irreversiblesecondarydamage.Eyesareorgans,forwhichhealing of injury would be completely meaningless if photoreceptor functions are lost. Thus, in order to maintain normal retinal functions, it is important how an ophthalmic inflammation and the ing secondary reaction can be controlled with the least amount of damage.

Along with the calming or ssion of an ophthalmic mation, a retinochoroidal fibrotic scar is often formed in epiretinal, intraretinal, or subretinal tissue and in some cases leads to a disorder in photoreceptor cell functions.

Collagen, which is one of the components of the stroma and retinal pigment epithelial cells, particularly type I en, is known as a representative cell component constituting a retinochoroidal fibrotic scar. choroidal dysfunction occurs due to the formation and atrophy of a choroidal fibrotic scar. In this regard, it is considered effective against retinochoroidal disorders to inhibit atrophy of collagen, particularlytypeIcollagen,ofretinalpigmentepithelialcells or the like to prevent deformation or disintegration of a tissue structure.

To date, a medicament for the prevention and/or treatment of diabetic retinopathy or lated macular ration having an agonist of a ic acid receptor (hereinafter, also referred to as "RAR"), all-trans retinoic acid or 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalenyl) oyl]benzoicacid,asaneffectiveingredient (for example, see Patent Literature 1). However, since such an effective ingredient does not have selectivity with respect to RAR subtypes RARα and RARβ, the contribution of each RAR subtype to improvement in the l function is unknown. Meanwhile, RAR is involved in various effects such as growth, morphogenesis, and differentiation in many cells such as inflammatory cells, immune cells, and structural cells. Further, it is verified that there is a difference in the distribution of RAR subtypes depending on the tissue or organ of a mammal. Some of the effects of RAR are undesirable, such as increase in triglyceride due to RARα.

Thus, the specificity or ivity with respect to subtypes in compounds with RAR agonist activity is expected to lead to reduction in risk of side effects. For the above reasons, there is a demand for RAR agonists, which have a strong effect of inhibiting retinochoroidal disorders and are highly safe based on subtype selectivity.

(E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid is disclosed to be useful as a RARγ selective agonist againstpulmonary emphysema,cancer,anddermatosis (for example, see Patent Literature 2) and against neurological pain (for example, see Patent Literature 3). r, there is no study that has examined the pharmacological effect of (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid, an ester thereof, or a salt thereof on retinochoroidal disorders, ularlytheformationandatrophyofaretinochoroidalscar, or a document suggesting such an effect.

[Citation List] t Literature] [PTL 1] Domestic Publication of PCT International Publication No. 2007/037188 [PTL 2] International Publication No. pamphlet [PTL 3] International Publication No. pamphlet [Summary of Invention] [Technical Problem] The objective of the present invention is to provide an inhibitor for a retinochoroidal disorder, particularly an tor for the formation and atrophy of a retinochoroidal scar in epiretinal, intraretinal, or inal tissue; and/or to at least provide the public with a useful choice.

[Solution to Problem] The search for a drug that is effective t ophthalmic diseases, particularly retinochoroidal disorders in vitreoretinal diseases, is an objective that is ant and of interest in the field of lmology. After diligent research to find a drug that is effective in inhibiting retinochoroidal disorders, particularly the formation and atrophy of a retinochoroidal scar, the inventors discovered that the RARγ selective agonist (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid exerts an excellent effect of amelioration in inhibiting the formation and atrophy of a retinochoroidal scar by pharmacological tests using murine retinal pigment epithelial cells, wherein the above-described benzoic acid exhibited an effect of inhibiting collagen atrophy and an effect of ting the ion and atrophy of subretinal scars in mice to complete the t invention.

Specifically, in a first aspect the present invention provides a use of palovarotene ((E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid), an ester thereof, or a salt thereof, in the manufacture of a ment for preventing or reducing scar formation or atrophy in a t having a retinochoroidal disorder. [0009a] In a second aspect the t invention provides a use of palovarotene ((E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid), an ester thereof, or a salt thereof, in the manufacture of a medicament for preventing or reducing scar formation on the retina and/or choroid of a subject, wherein said scar formation on the retina and/or d is caused by inflammation, hemorrhage, infection, or surgery in an ophthalmic tissue. [0009b] Also described is [1] an inhibitor for a retinochoroidal disorder comprising (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid, an ester thereof, or a salt thereof as an effective ingredient, the inhibitor for a retinochoroidal disorder of the above-described [1], wherein the (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid, the ester thereof, or the salt thereof is (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid or a salt thereof, [3] the inhibitor for a retinochoroidal disorder of the above-described [1] or [2], n the retinochoroidal disorder is ion or atrophy of a retinochoroidal scar in epiretinal, intraretinal, or inal , [4] the inhibitor for a choroidal disorder according to any one of the above-described [1]-[3], wherein a form of administration is instillative stration or oral administration, and [5] the inhibitor for a retinochoroidal disorder accordingly to any one of the above-described [1]-[4], wherein a dosage form is an instillation, an ophthalmic ointment, an injection, a tablet, a granule, a fine granule, a powder or a e.

[Advantageous Effects of Invention] (2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid, an ester thereof, or a salt thereof, which is an effective ingredient of the inhibitor for a retinochoroidal disorder as described herein, is useful as an inhibitor for retinochoroidal disorders, particularly as an inhibitor for the ion and atrophy of a retinochoroidal scar, by inhibiting collagenatrophyofaretinalpigmentepithelialcell,fibroblast, glial cell or the like.

[Brief Description of Drawings] [Figure 1] Figure 1 is a graph showing the relationship between the concentration (µM) of (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl- ,6,7,8-tetrahydronaphthaleneyl}vinyl)benzoic acid (hereinafter, also referred to as "benzoic acid of the invention") and collagen atrophy (diameter (mm) of collagen gel in the dish) when using murine retinal pigment epithelial cells, wherein"⃰"indicatesthepresenceofastatisticallysignificant ence (p < 0.05).

[Figure 2] Figure 2 is a graph showing the results of ng the effect of ting subretinal scar formation when the benzoic acid of the invention is injected in murine subretinal scar model production. Figure 2A shows the results of inal observation after 7 days from the injection of 50 µg of the benzoic acid of the present invention and macrophages. Figure 2B shows the results of measuring a subretinal scar region after 7 days from injection when injecting 1 µg, 5µg, or 50µg of the c acid of the invention and macrophages, wherein "⃰" indicates the presence of a statistically significant difference (p < 0.05).

[Description of Embodiments] The inhibitor for a retinochoroidal disorder described herein is not particularly limited and may be any inhibitor having the benzoic acid of the invention represented by the following formula (I), an ester thereof, or a salt thereof as the ive ingredient. However, the c acid of the invention or a salt f is preferable as an effective ingredient. Further, other embodiments described herein include: a method of treating a retinochoroidal disorder characterized in administering the benzoic acid of the invention, an ester thereof, or a salt f to a subject; the c acid of the invention, an ester thereof, or a salt f for use as an inhibitor for a retinochoroidal disorder; and use of the benzoic acid of the invention, an ester f, or a salt thereof in the preparation of an inhibitor for a retinochoroidal disorder.

[Chemical 1] In the present invention, a retinochoroidal disorder refers to a condition in which an injury occurs to a photoreceptor cell, ganglion cell, retinal pigment epithelial cell or tissue comprised of each of the above-described cells in the retina or choroid, tely leading to cell death or tissue dysfunction to cause disturbance in visual function such as vision or field of vision. A retinochoroidal disorder is suitably exemplified by formation and atrophy of a retinochoroidal scar and vitreoretinal diseases such as diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreoretinopathy, uveitis, ocular infection, retinopathy of prematurity, neovascular maculopathy, and retinochoroiditis. A retinochoroidal disorder is particularly suitably exemplified by ion and y of a retinochoroidal scar.

In the present invention, a retinochoroidal scar is a fibrous connective tissue occurring at an epiretinal, intraretinal, or inal injury site with the soothing or progression of an ophthalmic inflammation, preferably a fibrous connective tissue occurring at a subretinal injury site, and is mainly tissue comprisedofaretinalpigmentepithelialcell,fibroblast,glial cell, or the like with extracellular matrix including en.

In addition, the above-described epiretinal refers to on a retinal surface, subretinal refers to between the retina and choroid, inside the choroid, and under the choroid. r, formation of a retinochoroidal scar refers to the formation of a fibrous connective tissue at an epiretinal, intraretinal, or subretinal injury site with the soothing or progression of an ophthalmic inflammation. Atrophy of a retinochoroidal scar refers to the atrophy by a formed retinochoroidal scar pulling tissue in the periphery thereof upon healing. Such formation and atrophy of a retinochoroidal scar occurs in . It is possible to prevent peripheral tissue and macular area of a retinochoroidal scar from deforming to cause a disorder in the retinochoroidalfunctionbyinhibitingtheformation and atrophy of the retinochoroidal scar.

The benzoic acid of the invention, an ester thereof, or a salt thereof, which is an effective ingredient of the therapeutic agent for a retinochoroidal er of the present invention, can be manufactured in accordance with the method described in Patent Literature 2 described above or purchased as a commercially-available product. Examples of such cially-available products include product name: palovarotene manufactured by Shanghai Haoyuan Chemexpress.

Esters in the benzoic acid of the ion, an ester thereof, or a salt thereof, which is an effective ingredient of the therapeutic agent for a retinochoroidal disorder of the present invention, are not ularly limited and can be any ester converted to the benzoic acid of the ion in a reaction by an enzyme or the like under physiological conditions in vivo.

Examples of such esters include: esters generated by reaction with a primary alcohol, such as methanol, l, propanol, l, dodecanal or the like; esters generated by reaction with a secondary alcohol such as isopropanol, s-butanol, 1-ethylpropanol or the like; esters generated by reaction with a tertiary alcohol such as t-butanol, 1-methylethylpropanol orthelike;andestersgeneratedbyreactionwithanaminoalcohol such as 2-aminoethanol or the like.

The above-described esters can be manufactured by a known method from the benzoic acid of the invention or an intermediate during synthesis f.

Salts in the benzoic acid of the invention, an ester thereof, or a salt thereof, which is an effective ingredient of the inhibitorforaretinochoroidaldisorderofthepresentinvention, are not particularly d and can be any pharmaceutically acceptable salts. Such salts include (1) as an acid addition salt, inorganic acid salts such as hydrochloride, hydrobromic acid salt, hydro iodic acid salt, nitric acid salt, sulfuric acid salt, phosphoric acid salt and the like; and organic acid salts such as acetic acid salt, oroacetic acid salt, benzoic acid salt, oxalic acid salt, malonic acid salt, succinic acid salt, maleic acid salt, c acid salt, tartaric acid salt, citric acid salt, esulfonic acid salt, ethanesulfonic acid salt, trifluoromethanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt, glutamic acid salt, aspartic acid salt and the like and (2) as a basic salt, metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt and the like; inorganic salts such as ammonium salt and the like; and organic amine salts such as triethylamine salt, guanidine salt and the like.

The inhibitor for a retinochoroidal disorder of the present invention can be administered orally or parenterally (intravenous administration, uscular administration, intraperitoneal administration, percutaneous administration, racheal administration, intracutaneous administration, or subcutaneous administration) in a form of an ointment (preferably ophthalmic ointment), injection, , granule, fine granule, powder, capsule, inhalant, syrup, pill, liquid formulation, suspension, emulsion, percutaneous absorption agent, suppository, or lotion manufactured by mixing in a suitable pharmacologically acceptable additive. These formulations are manufactured by a well-known method by using an ve such as an excipient, lubricant, binding agent, disintegrator, emulsifier, izer, ing agent or diluent.

Examples of excipients include organic excipients and inorganic excipients. Examples of organic excipients include: sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol and the like; starch derivatives such as corn starch, potato starch, α-starch, dextrin and the like; cellulose derivatives such as crystalline cellulose and the like; gum arabic; dextran; pullulan and the like. Examples of nic excipients include: light anhydrous silicic acid; and ic acid salts such as m sulfate and the like. es of lubricants include: stearic acid; metal salts of c acid such as calcium stearate, magnesium stearate and the like; talc; colloidal silica; wax such as beeswax, spermaceti and the like; boric acid; adipic acid; sulfuric acid salts such as sodium sulfate and the like; glycol; fumaric acid; sodium benzoate; D,L-Leucine, sodium lauryl sulfate; silicic acids such as silica and silicic acid hydrate; and the starch derivatives and the like for the above-described excipients.

Examples of g agents include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol and the compounds described above shown for excipients. es of disintegrators include: cellulose tives such as hydroxypropyl cellulose with a low degree of substitutions, carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally crosslinked calcium carboxymethyl cellulose and the like; crosslinked polyvinylpyrrolidone; and chemically modified starch or cellulose derivatives or the like such as carboxymethyl starch and sodium carboxymethyl starch and the like.

Examples of emulsifiers include: dal clay such as bentonite and veegum and the like; anionic surfactants such as sodium lauryl sulfate and the like; cationic surfactants such as benzalkonium chloride and the like; and non-ionic surfactants andthelikesuchaspolyoxyethylenealkylether,polyoxyethylene sorbitan fatty acid ester, and e fatty acid ester and the like.

Examples of stabilizers include: para-hydroxybenzoic acid esters such as methylparaben, propylparaben and the like; alcohols such as chlorobutanol, benzyl l, and phenylethyl alcohol and the like; konium chloride; phenols such as phenol and cresol and the like; thimerosal; acetic anhydride; and sorbic acid.

Examples of flavoring agents include: sweeteners such as sodium rin and aspartame and the like; acidulants such as citric acid, malic acid, and tartaric acid and the like; and flavors such as menthol, lemon extract and orange extract and the like.

Diluents are generally compounds used as a diluent. Examples thereof include lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, mixtures f and the like.

For ointments (preferably lmic ointments), a commonly-used base such as white petrolatum or liquid paraffin or the like can be used for preparation.

The inhibitor for a retinochoroidal disorder of the present invention includes those in a form of instillation in addition to the above-described dosage forms. The above-described instillation can be instillatively administered. The agent can be formulated with a well-known method by suitably blending in an isotonizing agent, buffer, pH regulator, solubilizer, thickener, stabilizer, preservative (antiseptic) or the like as an additive. Further, it is also possible to obtain a stable instillation by adding a pH regulator, ner, dispersant or the like to prepare suspension of a drug.

Examples of isotonizing agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

Examples of buffers include phosphoric acid, ate, citric acid, acetic acid, ε-aminocaproic acid and the like.

Examples of pH regulators e hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium ide, ium hydroxide, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen ate, sodium carbonate, sodium bicarbonate and the like.

Examples of solubilizers include polysorbate 80, polyoxylethylene enated castor oil 60, macrogol 4000 and the like.

Examples of thickeners and sants include: cellulose rs such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like; polyvinyl alcohols; polyvinylpyrrolidone and the like. Further, examples of stabilizers include edetic acid, sodium edetate and the like.

Examples of preservatives (antiseptics) include commonly-used sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol and the like. It is also possible to use these preservatives in combination.

An instillation may have any pH within a range acceptable for an ophthalmic formulation, but the pH is bly set to 4.0-8.5.

The dosage of the inhibitor for a retinochoroidal disorder of the present invention can be appropriately changed in accordance with the dosage form, severity of symptoms of a t to whom the agent is to be administered, age, weight, judgment of a physician or the like. For oral agents, it is generally possible to administer 0.01-5000 mg, preferably 0.1-2500 mg, and more preferably 00 mg per day for an adult in one or several doses. For instillations, it is possible to ster thosewithaneffectiveingredientconcentration of 0.000001-10% (W/V), ably 0.00001-3% (W/V), and more preferably -1% (W/V), in one or several daily doses. For ophthalmic ointments, it is possible to administer those with an effective ingredient concentration of 0.00001-10% (W/W), preferably 0.0001-3% (W/W), and more preferably 0.001-1% (W/W), in one or several daily doses.

Hereinafter, the present inventionis illustratedin r detail while providing Examples (Test Examples and Drug Formulation Examples). However, the scope of the present invention is not d thereto.

Example 1 (Test on inhibition of three-dimensional en gel atrophy in murine l pigment epithelial cell) Murine retinal pigment epithelial cells were used to assess the inhibition effect of a tested nd on three-dimensional collagen gel atrophy in accordance with the method of Nishida etal(InvestigativeOphthalmology&VisualScience42:1247-1253 (2001)). A subretinal sheet-like pigment epithelial cell comprising a retinal pigment epithelial cell from a mouse eyeball was collected and grown in primary culture. The cultured cell was ed and ted from a culture slide with 0.05% Trypsin-EDTA. After washing twice in a serum free medium (MEM: product number 11095; Gibco), a serum-free medium was added to make a cell suspension. Type I collagen (3 mg/ml: product number 637-00653; Nitta Gelatin Inc.), 10 × MEM, reconstitution buffer (product number 791; Nitta Gelatin Inc.), cell suspension (1.1 × 107 cells/ml in MEM), and water were mixed on ice at the volume ratio of 7:1:1:0.2:1.8. A culture dish coated with 1% BSA was inoculated with the mixture (0.5 ml), which was incubated for one hour at 37°C to make a collagen gel. Then, 0.5 ml each of serum free media, to which 1 ng/ml of TGF-β2 (R&D) and 0, 0.01, 0.1, or 1 µM of the benzoic acid of the invention were added, was added onto collagen gels and incubated at 37°C. The diameter of gels was measured after 24 hours. As a control, 0.5 ml of only a serum-free medium was added and similarly incubated.

The results are shown in Figure 1.

It can be seen from Figure 1 that the benzoic acid of the invention can inhibit collagen atrophy due to TGF when using murine retinal pigment epithelial cells. This demonstrates that the c acid of the invention contributes to collagen turn over and is effective in ting retinochoroidal disorders and has an effect of inhibiting tissue remodeling that occurs after inflammation, hage, infection, surgery, or injury in an ophthalmic tissue, i.e., retinal tissue fibrillation, retinochoroidal scar formation, and y.

Example 2 (Test on inhibition of murine inal scar formation) A murine subretinal scar model was produced to study r the benzoic acid of the invention has an effect of inhibiting subretinal scar formation. A subretinal scar model in a mouse was produced by the method shown below in ance with the method of Young-joon et al (Investigative Ophthalmology & Visual Science, 52, 6089-6095(2001)).

(Production of murine subretinal scar model) First, laser was irradiated (0.05 seconds, 200 mW, 532 nm) onto one location on the posterior pole of fundus of mouse C57BL/6 (purchased from SLC) to destroy the Bruch's membrane, which enabled infiltration of inflammatory cells from the choroid as well as on of air bubbles subretinally.

A 33G needle was then inserted from pars plana. 0.5 µl of 4 × 107 ml thioglycollate elicited peritoneal macrophage and 1 µg, 5 µg, or 50 µg of the c acid of the invention were subretinally injected. For the control, the benzoic acid of the invention was not injected (0 µg).

The subretinal area was observed and subretinal scar region was measure 7 days after injection of the macrophage and the benzoic acid of the invention described above. The results are shown in Figure 2.

(Results) As shown in Figure 2A, formation of a scar was inhibited when 50 µg of the benzoic acid of the invention was injected in comparison to the control. Further, as shown in Figure 2B, the scar region (fibrillation region) narrows as the amount of injection of the c acid of the invention increases. Thus, it was revealed that formation and atrophy of subretinal scars can be inhibited by the benzoic acid of the invention.

Example 3 [Drug Formulation Example] (Drug Formulation Example 1) Instillation In 100 ml Benzoic acid of the ion 100 mg Sodium chloride 800 mg Polysorbate 80 appropriate amount Disodium hydrogen phosphate riate amount Sodium dihydrogen phosphate appropriate amount Sterile purified water appropriate amount The benzoic acid of the invention and the other ents described above are added to sterile purified water. The solution is thoroughly mixed to prepare an instillation. It is possible to e an instillation with a concentration of 0.05% (W/V), 0.3% (W/V), 0.5% (W/V), or 1% (W/V) by changing the amount of the benzoic acid of the invention or the like that is added.

(Drug Formulation Example 2) Ophthalmic Ointment In 100 g Benzoic acid of the invention 0.3 g Liquid paraffin 10.0 g White petrolatum appropriate amount The c acid of the invention is added to homogeneously-melted white petrolatum and liquid paraffin. The mixture is thoroughly mixed and then lly cooled to prepare an ophthalmic ointment. It is le to prepare an ophthalmic ointment with a concentration of 0.05% (W/W), 0.1% (W/W), 0.5% (W/W), or 1% (W/W) by changing the amount of the c acid of the invention or the like that is added.

(Drug Formulation Example 3) Tablet In 100 mg Benzoic acid of the invention 1 mg Lactose 66.4 mg Corn starch 20 mg Calcium carboxymethyl cellulose 6 mg Hydroxypropyl cellulose 6 mg Magnesium stearate 0.6 mg The benzoic acid of the invention, corn starch and lactose are mixed in a mixer. Calcium ymethyl cellulose and hydroxypropylcelluloseareaddedtothemixtureforgranulation.

The particle size of the resulting granules is adjusted after drying. Magnesium stearate isadded to and mixed with the ed granules and the mixture is made into tablets with a ing machine. Further, it is possible to prepare tablets with the content of 0.1 mg, 10 mg, or 50 mg in 100 mg by ng the amount of the benzoic acid of the invention or the like that is added.

[Industrial Applicability] (E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid, an ester thereof, or a salt thereof, which is an effective ingredient of the inhibitor for a retinochoroidal disorder of the present invention, is useful as an inhibitor for retinochoroidal disorders, particularly as an inhibitor for the formation and y of a retinochoroidal scar, by strongly inhibiting en contraction in a retinal pigment epithelial cell, fibroblast, glial cell or the like in the retinochoroid.

The term “comprising” as used in this specification and claims means sting at least in part of”. When interpreting statements in this ication, and claims which include the term “comprising”, it is to be tood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of ing a context for discussing the features of the invention. Unless specifically stated otherwise, nce to such external documents is not to be construed as an admission that such documents, or such sources of ation, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Claims

[Claims]

1. Use of palovarotene ((E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) c acid), an ester thereof, or a salt thereof, in the manufacture of a medicament for preventing or ng scar ion or atrophy in a subject having a retinochoroidal disorder.

2. The use of claim 1, wherein the medicament prevents or reduces retinochoroidal scar formation.

3. The use of claim 1 or 2, wherein the scar is a connective tissue in an epiretinal, intraretinal, and/or subretinal site.

4. The use of any one of claims 1-3, wherein the scar comprises a retinal pigment epithelial tissue, a fibroblast tissue, a glial tissue, photoreceptor cells, and/or ganglion cells.

5. Use of palovarotene -(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid), an ester thereof, or a salt thereof , in the manufacture of a medicament for preventing or reducing retinal and/or choroid tissue damage in a subject having a retinochoroidal disorder.

6. Use of palovarotene ((E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid), an ester thereof, or a salt thereof , in the manufacture of a medicament for suppressing collagen atrophy and/or en contraction in a subject having a retinochoroidal er.

7. The use of claim 6, wherein the collagen atrophy and/or collagen contraction is in an epiretinal, intraretinal, and/or subretinal site.

8. The use of claim 6 or 7, wherein the collagen atrophy and/or collagen contraction is in a retinal pigment epithelial , a fibroblast tissue, and/or a glial , photoreceptor cells, and/or ganglion cells.

9. The use of any one of claims 1-8, wherein said retinochoroidal disorder is a vitreoretinal e.

10. The use of claim 9, wherein said vitreoretinal disease is diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreoretinopathy, uveitis, ocular infection, retinopathy of prematurity, neovascular maculopathy, or retinochoroiditis.

11. Use of palovarotene ((E)(2-{3-[(1H-pyrazoleyl)methyl]-5,5,8,8-tetramethyl -5,6,7,8-tetrahydronaphthaleneyl}vinyl) benzoic acid), an ester thereof, or a salt thereof, in the manufacture of a medicament for preventing or ng scar formation on the retina and/or choroid of a subject, wherein said scar formation on the retina and/or choroid is caused by inflammation, hemorrhage, infection, or surgery in an ophthalmic tissue.

12. The use of claim 11, wherein said scar formation on the retina and/or choroid is caused by surgery.

13. The use of any one of claims 1-12, n the medicament prevents deformation or disintegration of a tissue structure.

14. The use of any one of claims 1-13, wherein the medicament ts tissue remodeling that occurs after inflammation, hemorrhage, infection, surgery, or injury in an lmic tissue.

15. The use of any one of claims 1-14, wherein the medicament is formulated for administration orally, intravenously, intramuscularly, intraperitoneally, aneously, intratracheally, intracutaneously, subcutaneously, or by instillation.

16. The use of any one of claims 1-15, wherein the medicament is in the form of an ointment, injection, tablet, granule, fine granule, powder, capsule, inhalant, syrup, pill, liquid ation, suspension, emulsion, percutaneous absorption agent, suppository, lotion, or instillation.

17. The use of claim 16, wherein said ointment is an ophthalmic ointment.

18. The method of claim 17, wherein the concentration of said palovarotene, or ester or salt f, in the ophthalmic ointment is from 0.00001% to 10% (w/w).

19. The use of claim 18, wherein the concentration of said palovarotene, or ester or sale thereof, in the ophthalmic nt is from 0.0001% to 3% (w/w).

20. The use of claim 19, wherein the tration of said rotene, or an ester or salt thereof, in the ophthalmic ointment is from 0.001% to 1% (w/w).

21. The use of claim 20, wherein the concentration of said palovarotene, or an ester or salt f, in the ophthalmic ointment is 0.05% (w/w), 0.1% (w/w), 0.5% (w/w), or 1% (w/w).

22. The use of any one of claims 17-21, wherein the ophthalmic ointment comprises a solubilizer.

23. The use of claim 22, wherein the solubilizer is selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000.

24. The use of claim 23, wherein the solubilizer is polysorbate

25. The use of claim 16, wherein said medicament is in the form of a liquid formulation.

26. The use of claim 25, wherein the concentration of said palovarotene, or an ester or salt thereof, in the liquid formulation is from 0.000001% to 10% (w/v).

27. The use of claim 26, wherein the concentration of said palovarotene, or an ester or salt thereof, in the liquid formulation is from 1% to 3% (w/v).

28. The use of claim 27, wherein the concentration of said rotene, or an ester or salt thereof, in the liquid formulation is from 0.0001% to 1% (w/v).

29. The use of claim 28, wherein the concentration of said palovarotene, or an ester or salt thereof, in the liquid formulation is 0.05% (w/v), 0.3% (w/v), 0.5% (w/v), or 1% (w/v).

30. The use of any one of claims 25-29, wherein the liquid ation comprises a solubilizer.

31. The use of claim 30, wherein the solubilizer is selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000.

32. The use of claim 31, wherein the solubilizer is polysorbate

33. The use of claim 15, wherein the ment is formulated for administration orally.

34. The use of claim 33, wherein said palovarotene, or an ester or salt thereof, is in an amount of from 0.01 to 5000 mg.

35. The use of claim 34, wherein said palovarotene, or an ester or salt thereof, is in an amount of from 0.1 to 2500 mg.

36. The use of claim 35, wherein said palovarotene, or an ester or salt f, is in an amount of from 0.5 to 1000 mg.

37. The use of claim 16, wherein said medicament is in the form of an injection.

38. The use of any one of claims 1-37, wherein the medicament is formulated for administration in one or more daily doses.

39. A use as d in any one of claims 1-38 substantially as described with reference to any example thereof. -