WO2014174747A1 - 眼底疾患治療剤 - Google Patents
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Definitions
- the present invention relates to a drug for preventing or treating ocular fundus disease, particularly diabetic retinopathy or age-related macular degeneration.
- Diabetic retinopathy is one of the three major complications of diabetes together with diabetic nephropathy / neuropathy, and is the second most common cause of blindness in adults after glaucoma in Japan. ing.
- DR diabetic retinopathy
- hyperglycemia oxygen does not spread throughout the retina, and the retina is deficient. Fall into.
- new blood vessels new blood vessels grow and try to make up for the lack of oxygen, but the new blood vessels are brittle and easily bleed, causing a membrane (proliferating tissue) like a scab on the retina. May cause retinal detachment (proliferative diabetic retinopathy).
- Diabetic retinopathy is classified into three major stages depending on the degree of progression: simple diabetic retinopathy, preproliferative diabetic retinopathy, and proliferative diabetic retinopathy, but even in the diabetic retinopathy stage, it is mainly due to increased vascular permeability. Since macular edema, macular edema, and hard macular erythema can develop (diabetic macular edema, diabetic macular disease), diagnosis based on fundus findings is important in any case. Here, it is known that diabetic macular edema develops regardless of the stage of diabetic retinopathy. The pathological condition is the accumulation of plasma components leaked from the retinal blood vessels due to increased vascular permeability in the macular region, causing subjective symptoms such as distortion and reduced visual acuity.
- Treatment of diabetic retinopathy may be improved by controlling blood glucose levels in simple diabetic retinopathy, but retinal photocoagulation is often required in preproliferative diabetic retinopathy.
- vitrectomy is performed for the purpose of removing bleeding or proliferating tissue in the eye or restoring the detached retina.
- the current situation is that the good visual function has not yet been maintained.
- Age-related Macular Degeneration is a disease in which waste accumulates under the retinal pigment epithelium due to aging, thereby causing direct or indirect damage to the macular region. Is the number one cause of blindness in adults.
- age-related macular degeneration There are two types of age-related macular degeneration: dry type (wet type) and wet type (wet type).
- the atrophic type gradually atrophys the retinal pigment epithelium, and the retina is damaged and has poor vision. It is a gradual declining disease, and no effective treatment is currently known.
- One exudation type is a disease in which abnormal blood vessels (choroidal neovascularization) invade from the choroid under the retinal pigment epithelium or between the retina and the retinal pigment epithelium and damage the retina. In choroidal neovascularization, blood components are leaked and liquid is stored under the retina (subretinal fluid), or blood vessels are broken and bleeding into the retina (retinal hemorrhage). Decreases
- VEGF inhibitors In these diabetic retinopathy or age-related macular degeneration, retinal neovascularization or choroidal neovascularization is greatly involved in the pathological condition, respectively, and therefore treatments aimed at suppressing or inhibiting angiogenesis have been attempted. Intravitreal injection of the above-mentioned VEGF inhibitor has already been applied in Japan for age-related macular degeneration, and clinical trials of VEGF inhibitors are also progressing for diabetic retinopathy.
- Rho kinase Rho-associated protein kinase: ROCK
- ROCK Rho-associated protein kinase
- Non-Patent Documents 4 and 5 Y-27632 has also been shown to inhibit retinal neovascularization by intravitreal administration to hyperoxia-induced retinopathy model mice (Non-patent Document 6).
- retinopathy, diabetic retinopathy, macular degeneration, etc. are mentioned as uses of novel ROCK inhibitors disclosed in several patent documents, but specific effects on these diseases are mentioned in this document. Is not shown (Patent Documents 1 to 3).
- the present invention relates to providing a new drug for preventing or treating ocular fundus disease, particularly diabetic retinopathy or age-related macular degeneration.
- the present invention relates to the following inventions.
- 1) For ocular fundus diseases comprising (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof as an active ingredient Prophylactic or therapeutic agent.
- 2) The preventive or therapeutic agent according to 1) above, wherein the fundus disease is diabetic retinopathy.
- the preventive or therapeutic agent according to 1) above, wherein the fundus disease is diabetic macular edema.
- the preventive or therapeutic agent according to 1) above, wherein the fundus disease is age-related macular degeneration.
- medical agent for the prevention or treatment of a fundus disease especially diabetic retinopathy or age-related macular degeneration
- the eye drops are effective even when administered in a small amount of eye drops, and not only the effectiveness but also the patient is administered without causing great physical and mental pain. It can be administered non-invasively and is extremely useful as a therapeutic and / or prophylactic agent for fundus diseases that can be easily administered to elderly people and children.
- FIG. 2 is a representative photographed image of a physiological saline ophthalmic group (control), a 0.4% solution ophthalmic group of Compound 1 and a 0.8% solution ophthalmic group of Compound 1 by a flat mount. It is the result of having quantified the retinal ischemia area
- shaft shows the ratio of the non-perfusion area
- the vertical axis shows the ratio of the neovascular area where the physiological saline eye drop group is 100%. Numerical values are expressed as mean ⁇ standard deviation, ** indicates that the p-value is less than 0.01, C. Indicates no significant difference. It is the typical picked-up image of the physiological saline eye drop group (control) by flat mount, and the 0.4% solution eye drop group of fasudil. It is the result of having quantified the retinal ischemia area
- shaft shows the ratio of the non-perfusion area
- FIG. 2 is a representative photographed image of a physiological saline eye drop group (control) and a 0.8% solution eye drop group of Compound 1 by fluorescence fundus imaging. It is the result of having quantified the neovascular region of each eye drop group by fluorescent fundus angiography.
- the vertical axis shows the ratio of the neovascular area where the physiological saline eye drop group is 100%. The numerical value is expressed as an average value ⁇ standard error, and * indicates that the p value is less than 0.05. It is the result of quantifying choroidal neovascularization of each eye drop group by fluorescent fundus angiography.
- the vertical axis represents choroidal neovascularization volume ( ⁇ m 3 ). Numerical values show mean ⁇ standard error.
- FIG. 2 is a representative photographed image of a normal mouse (reference), a physiological saline eye drop group (control), and a 0.8% solution eye drop group of Compound 1 by fluorescence fundus contrast imaging and optical coherence tomography.
- (S)-( ⁇ )-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine used in the present invention is a cerebrovascular therapeutic agent, substance P antagonistic action, leukotriene D 4
- a compound having an antagonistic action and a Rho kinase inhibitory action can be produced by a known method, for example, the method described in International Patent Publication No. 99/20620 pamphlet (Patent Document 4).
- Examples of the salt of (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine include hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, bromide.
- Salts of inorganic acids such as hydrogen acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfone
- inorganic acids such as hydrogen acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfone
- examples include salts with organic acids such as acids, and hydrochlorides are particularly preferable.
- (S)-( ⁇ )-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof is not only an unsolvated form but also a hydrate or a solvate Can exist as well. Hydrates are preferred, but in the present invention, all crystal forms and hydrates or solvates are included.
- fundus disease refers to lesions that mainly develop in the retina and / or choroid.
- fundus diseases include retinal vein occlusion such as fundus changes due to hypertension and arteriosclerosis, central retinal artery occlusion, central retinal vein ococlusion and branch retinal vein ococlusion Dysfunction, diabetic retinopathy, diabetic macular edema, diabetic macular edema, Ealesasedisease, Coats disease and other retinal vascular congenital anomalies, Hippel disease (von Hippel disease), pulseless disease, Macular disease (central serous chorioretinopathy), cystoid macular edema, age-related macular degeneration, macular hole, myopic macular atrophy (myopic) macular degeneration), retinal vitreous interface macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, etc.), retinal detachment, retinal pigment (eg hiatogenic, traction, exudative) Sex, retinopathy of prematurity, and the like.
- retinal vein occlusion
- a preparation of (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof is also known It can be prepared according to the method.
- eye drops can be prepared using isotonic agents, buffers, surfactants, preservatives and the like as necessary.
- the pH only needs to be within the range acceptable for ophthalmic preparations, and is preferably in the range of pH 4-8.
- the preparation of the present invention is preferably used for ophthalmic preparations, particularly for eye drops.
- eye drops include aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments and the like. Either is acceptable.
- Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, especially an eye drop acceptable carrier, such as an isotonic agent, a chelating agent, a stabilizer, pH A regulator, preservative, antioxidant, solubilizer, thickening agent, and the like can be blended and manufactured by (formulation) methods known to those skilled in the art.
- the active ingredient of the present invention is effective even in a small amount of ophthalmic administration, and can be an eye drop.
- the eye drop of the present invention comprises (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, which is the active ingredient of the present invention And a carrier acceptable for eye drops.
- the desired components described above are dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil.
- an ointment base can be included in addition to the various components described above.
- the ointment base is not particularly limited, but is an oily base such as petroleum jelly, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying a cocoon oil phase and an aqueous phase with a surfactant, etc .; hydroxypropylmethylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.
- (S)-( ⁇ )-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof is used for ocular fundus disease, particularly diabetic retinopathy or addition.
- the dosage When used for the prevention or treatment of age-related macular degeneration, the dosage varies depending on the body weight, age, sex, symptoms, dosage form, number of administrations, etc.
- the number of administrations is not particularly limited, but it is preferable to administer once or several times. In the case of liquid eye drops, one to several drops may be instilled at a time.
- the present invention will be described in more detail, but the present invention is not limited thereto.
- Example 1 Effects on hyperoxia-induced retinopathy model mice (Mice OIR (oxygen-induced retinopathy) model) (S)-(-)-1-() in the Mice OIR Model widely used as a model for ischemic retinopathy such as diabetic retinopathy
- S oxygen-induced retinopathy
- Compound 1 4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine
- test compound solution Preparation of Compound 1 Solution
- Compound 1 Solution A predetermined amount of (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine monohydrochloride dihydrate, glycerin After dissolving in purified water, sodium dihydrogen phosphate and sodium hydroxide were added to bring the solution to pH 6.0 to prepare a compound 1 solution having a desired concentration.
- Test Method A Drugs and animals used in the test Compound 1 solution: 0.4% solution, 0.8% solution (eye drop amount: 20 ⁇ l) Fasudil solution: 0.4% solution (eye drop amount: 20 ⁇ l)
- Experimental animals C57BL / 6JJcl mice (sex: male, 8-14 mice per group)
- pentobarbital (Nembutal) was administered intraperitoneally, after euthanasia by overanesthesia, both eyes were removed and fixed to 4% paraformaldehyde (PFA) at 37 ° C. for 1 hour, and then the corneal ring The part was incised circumferentially, and the cornea and iris were removed from the eyeball. Subsequently, after fixing to 4% PFA at 37 ° C. for 1 hour, the lens and sclera / choroid were removed, and the retina was isolated with an eye cup. Further, the retina was fixed in 4% PFA at 37 ° C.
- PFA paraformaldehyde
- Non-perfusion region avascular region area / total retina area
- neovascular region neovascular region area / total retina area
- the animal In the fluorescence fundus contrast examination, the animal is first instilled with tropicamide to dilate the pupil, then anesthetized by intraperitoneal administration of ketalal 100 mg / kg and seractal 10 mg / kg, and fluorescein fluorescent fundus contrast medium 12 ⁇ l / g intraperitoneally. After injection, fluorescent fundus angiography photographs were taken with optos200TX (OPTOS PLC), and the neovascular area was calculated by NIH image J software using the above formula. The numerical values obtained were converted with the saline instillation group (control) as 100%, and statistical analysis was performed by the Wilcoxon test.
- FIGS. 1 to 3 show the results of instillation of the compound by flat mount
- FIGS. 4 to 6 show the results of fasudil instillation.
- FIG. 1 is a representative photographed image of a saline instillation group (control), a 0.4% solution instillation group of Compound 1, and a 0.8% solution instillation group of Compound 1, respectively. It can be seen that the retinal ischemic region (non-perfusion region) and the neovascular region are remarkably observed, whereas the 0.4% and 0.8% solution ophthalmic groups of Compound 1 are suppressed. 2 and 3 show the results of quantification of the retinal ischemic region (non-perfusion region) and the neovascular region.
- FIG. 1 is a representative photographed image of a saline instillation group (control), a 0.4% solution instillation group of Compound 1, and a 0.8% solution instillation group of Compound 1, respectively. It can be seen that the retinal ischemic region (non
- Non-Patent Document 5 discloses the effect when fasudil is injected into the vitreous body, but the effect of eye drops could not be confirmed.
- FIGS. 7 is a representative photographed image of the saline instillation group (control) and the 0.8% solution instillation group of Compound 1, respectively, whereas the neovascular region is remarkably observed in the saline instillation group. It can be seen that the 0.8% solution ophthalmic solution of Compound 1 is suppressed.
- results shown in FIGS. 1 to 3, 7, and 8 indicate that the expression of the ischemic region and the neovascular region in the OIR model is remarkably suppressed by the instillation of Compound 1. Further, the results shown in FIGS. 4 to 6 indicate that the effect seen with Compound 1 is not observed with fasudil.
- Example 2 Effect on Choroidal Neovascularization Model Mice (Mice CNV (choroidal neovascularization) Model)
- Choroidal Neovascularization Model known as a model for age-related macular degeneration
- Test Method A Drugs and animals used in the test Compound 1 solution prepared in the same manner as in Example 1: 0.4% solution, 0.8% solution (eye drop amount: 20 ⁇ l)
- Experimental animals C57BL / 6JJcl mice (6-10 weeks old, male, 11-12 mice per group)
- the group composition was a saline instillation group (control), a 0.4% solution instillation group of Compound 1 and a 0.8% solution instillation group of Compound 1, and instillation was performed 3 times a day.
- the day of photocoagulation treatment was defined as day 0, and instilled from day 0 to day 7, a flat mount was created on day 7, and blood vessels were stained with FITC-lectin for evaluation. Specifically, the spot where bleeding or tissue destruction is observed is excluded, and the average value ( ⁇ m 3 ) per eye is calculated after calculating the CNV volume of each adoption example spot with NIS-Elements AR Version 4.13. did.
- Test Method A Drugs and animals used in the test Compound 1 solution prepared in the same manner as in Example 1: 0.8% solution (eye drop amount: 20 ⁇ l)
- Experimental animals Kimba mice (purchased from Lions Eye Institute Ltd., 6 animals per group)
- fluorescent fundus imaging first, the pupil of the mouse was dilated with tropicamide ophthalmic solution, then anesthetized by intraperitoneal administration of 100 mg / Kg of Ketalar and 10 mg / Kg of Selactal, and then fluorescein fluorescence After injection of 6 ⁇ l / g of contrast medium, fluorescence fundus contrast examination was performed with Heidelberg Retina Angiograph (HRA, Heidelberg, Germany).
- the mouse pupil was dilated with tropicamide ophthalmic solution and then anesthetized by intraperitoneal administration of ketalal 100 mg / Kg and seractal 10 mg / Kg, and 5 lines 6 mm length in X and Y axis was taken with The Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), and the averaged maximum retinal thickness was measured (statistical analysis was Student's t test).
- the upper part of FIG. 10 is a representative photographed image of each group by fluorescence fundus contrast imaging, and the lower part is an optical coherence tomography.
- an image of a normal mouse (left side, maximum retinal thickness in this example is 276 ⁇ m) is also shown. It can be seen that edema is observed in saline instillation and the retina is thickened, whereas instillation of 0.8% solution of Compound 1 suppresses edema and the retinal thickness is about the same as in normal mice.
- FIG. 11 is a graph of the numerical value of the retinal thickness.
- the average maximum retinal thickness of the saline instillation group (control) is 361.8 ⁇ 36.1 ⁇ m, whereas 0.8 of Compound 1 In the% solution ophthalmic group, it was found that the retina thickening was significantly suppressed to 256.7 ⁇ 35.7 ⁇ m.
- b-END3 (bEND.3: ATCC CRL-2299 (registered trademark)), a mouse brain microvascular endothelial cell, was subcultured in 3.5 cm dish (9 ⁇ 10 5 cells / dish). The test was started from the 6th day after passage.
- Drug treatment conditions are as follows: no treatment (indicated as control in the figure), VEGF stimulation example (25 ng / ml, 24 hours: indicated in the figure as VEGF (25 ng / ml 24 hours) stimulation), compound 1 (3 ⁇ M or 30 ⁇ M)
- Example of VEGF stimulation after pretreatment (3 hours) (25 ng / ml, 24 hours: VEGF + Compound 1 (3 ⁇ M 3 hours) pretreatment or VEGF + Compound 1 (30 ⁇ M 3 hours) pretreatment in the figure)
- IL-6 stimulation example 10 ng / ml, 24 hours: IL-6 (denoted as 10 ng / ml 24 hours) stimulation in the figure) and Compound 1 (30 ⁇ M) pretreatment (3 hours) and IL-6 stimulation example (10 ng / ml, 24 hours: figure)
- the cells after the test were immunostained according to the following procedure, and the expression of claudin-5 or F-Actin was evaluated. That is, the cells after the test were treated with 100% methanol at room temperature for 5 minutes, further treated with 50% methanol for 5 minutes, and washed with PBS (5 minutes ⁇ 2 times). Next, trim the cover glass with a cotton swab, surround it with a Dako pen, and block with 10% normal goat serum ready-to-use (Invitrogen) (30 minutes, room temperature). Left at 4 ° C overnight.
- Rabbit anti-Claudin-5 antibody (Rabbit anti-Claudin-5 (Invitrogen 34-1600)) or rabbit anti-F-actin antibody (Rabbit anti-F-actin (Biossusa bs-1571R)) After 70 ⁇ L was added dropwise, it was washed with PBS (10 minutes ⁇ 3 times) and subjected to primary treatment. This was allowed to stand for 60 minutes at room temperature, protected from light, and treated with a secondary antibody at 200-fold dilution of Alexa Fluo488 (labeled anti-rabbit IgG FITC) (Alexa Fluo488 anti-Rabbit IgG FITC). Washed with PBS (10 minutes x 3 times). Nuclei were stained with DAPI, then covered with a crystal mount and photographed with a microscope ( ⁇ 400). The results for Cloading-5 are shown in FIG. 12, and the results for F-actin are shown in FIG.
- FIG. 12 shows the results of Claudin-5 immunostaining
- FIG. 13 shows the results of F-Actin immunostaining.
- FIG. 12 it can be seen that the expression of claudin-5, which is decreased by VEGF or IL-6 stimulation, is improved by the pretreatment with compound 1.
- FIG. 13 it can be seen that F-Actin polymerization caused by VEGF or IL-6 stimulation is suppressed by pretreatment with Compound 1. Therefore, it was found that Compound 1 can be expected to have an inhibitory effect on the breakdown of the intercellular barrier.
- the (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof according to the present invention is excellent in inhibiting angiogenesis. It has an action and is useful as a medicament for the prevention or treatment of ocular fundus diseases, particularly diabetic retinopathy or age-related macular degeneration.
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Abstract
Description
ここで、糖尿病黄斑浮腫は、糖尿病網膜症の病期に関わらず発症することが知られている。その病態は血管透過性亢進によって網膜血管から漏出した血漿成分の黄斑部への貯留であり、歪視や視力低下などの自覚症状が生じる。
また、4-フルオロ-5-環状アミノスルホニルイソキノリン誘導体に関しては、喘息治療剤、サブスタンスP拮抗剤、ロイコトリエンD4拮抗剤、Rhoキナーゼ阻害剤などの作用(特許文献3)や、脳血管障害治療剤(特許文献4)としての作用があることが知られているが、局所投与による選択的な作用については報告されていない。
1)(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を有効成分とする眼底疾患の予防又は治療剤。
2)眼底疾患が糖尿病網膜症である上記1)の予防又は治療剤。
3)眼底疾患が糖尿病黄斑浮腫である上記1)の予防又は治療剤。
4)眼底疾患が加齢黄斑変性である上記1)の予防又は治療剤。
5)点眼剤である上記1)~4)の予防又は治療剤。
6)(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物並びに薬学的に許容される担体を含有してなる眼底疾患予防又は治療のための医薬組成物。
7)眼底疾患が糖尿病網膜症である上記6)の医薬組成物。
8)眼底疾患が糖尿病黄斑浮腫である上記6)の医薬組成物。
9)眼底疾患が加齢黄斑変性である上記6)の医薬組成物。
10)点眼剤である上記6)~9)の医薬組成物。
11)(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする眼底疾患の予防又は治療方法。
12)投与が、点眼による投与である、上記の11)に記載の方法。
13)眼底疾患が糖尿病網膜症である、上記の11)又は12)に記載の予防又は治療方法。
14)眼底疾患が糖尿病黄斑浮腫である、上記の11)又は12)に記載の予防又は治療方法。
15)眼底疾患が加齢黄斑変性である、上記の11)又は12)に記載の予防又は治療方法。
17)眼底疾患の予防又は治療剤を製造するための、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物の使用。
18)眼底疾患の予防又は治療剤に使用するための、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物。
19)眼底疾患の予防又は治療剤が、点眼薬である、上記の17)又は18)に記載の使用、又は化合物。
20)眼底疾患が糖尿病網膜症である、上記の17)又は18)に記載の使用、又は化合物。
21)眼底疾患が糖尿病黄斑浮腫である、上記の17)又は18)に記載の使用、又は化合物。
22)眼底疾患が加齢黄斑変性である、上記17)又は18)に記載の使用、又は化合物。
本発明の医薬組成物は、特に点眼薬は、少量の点眼投与においても有効性を有しており、有効性だけでなく、患者に多大な肉体的かつ精神的な苦痛を与えることなく投与することが可能であり、非侵襲的投与が可能であり、老人や子供に対しても簡便に投与することができる眼底疾患の治療剤及び/又は予防剤として極めて有用である。
本発明の有効成分は、少量の点眼投与においても有効性を有しており、点眼薬とすることができる。本発明の点眼薬は、本発明の有効成分である(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物、及び点眼薬に許容される担体を含有するものである。
以下、本発明を更に詳しく説明するが、本発明はこれらに限定されるものではない。
高酸素誘発網膜症モデルマウス(Mice OIR(oxygen-induced retinopathy) Model)に対する効果
糖尿病網膜症などの虚血性網膜症モデルとして汎用されているMice OIR Modelにおける(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン(化合物1)の有効性を調べるため、以下の方法に従って検討した。
A.化合物1溶液の調製
所定量の(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン一塩酸塩・二水和物、グリセリンを精製水に溶解した後、リン酸二水素ナトリウム、水酸化ナトリウムを加えて溶液をpH6.0とし、所望の濃度の化合物1溶液を調製した。
上記A.化合物1溶液の調製において、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン一塩酸塩・二水和物の代わりに所定量のファスジル2塩酸塩(LC Laboratories)を用いて、所望の濃度のファスジル溶液を調製した。
A.試験に使用した薬剤及び動物
化合物1溶液:0.4%溶液、0.8%溶液(点眼量:20μl)
ファスジル溶液:0.4%溶液(点眼量:20μl)
実験動物: C57BL/6JJclマウス(性別:雄性、一群8~14匹)
同一日に出生したC57BL/6JJclマウスを、生後7日目から75%酸素環境で飼育し、生後12日目で通常の室内環境に移し、点眼を開始した。群構成は、生理食塩水点眼群(対照)、化合物1の0.4%溶液点眼群、化合物1の0.8%溶液点眼群、ファスジルの0.4%溶液点眼群であり、点眼は1日3回行った。生後17日目にフラットマウント又は蛍光眼底造影検査により網膜虚血領域(無灌流領域)及び新生血管領域を定量化して評価した。すなわち、ペントバルビタール(ネンブタール)1g/kgを腹腔内に投与し、過麻酔により安楽死後、両眼球を摘出し、4%パラホルムアルデヒド(Paraformaldehyde:PFA)に37℃で1時間固定した後、角膜輪部を円周状に切開し、眼球より角膜、虹彩を除去した。続いて4%PFAに37℃で1時間固定した後、水晶体、及び強膜・脈絡膜を除去し、網膜をeye cupで単離した。さらに網膜を4%PFAに37℃で3時間固定した後、PBSにて3回洗浄(各15分、37℃)、脱水(メタノール50%→100%各10分、37℃)、PBSにて3回洗浄(各15分、37℃)し、Blocking Buffer(1%BSA、0.5%Triton-X in PBS)にて60分(37℃)ブロッキングを行った。次いで一次抗体処置(0.7% FITC-conjugates Anti-lectin Ab in PBS、4℃、over night)し、PBSにて3回洗浄(各15分、37℃)後、eye cupに4-6カ所放射状切開を加え、フラットマウント状網膜にクリスタルマウントでカバーした。その後蛍光顕微鏡(BZ-9000, KEYENCE Corp, Osaka, Japan)で撮影し、NIH image J softwareにて網膜全体に対する無灌流領域及び新生血管領域を次式により算出した。得られた数値は生理食塩水点眼群(対照)を100%として換算し、統計解析はWilcoxon検定にて行った。
無灌流領域=無血管領域面積/網膜全体面積
新生血管領域=新生血管領域面積/網膜全体面積
フラットマウントによる化合物1点眼の結果を図1~図3に、ファスジル点眼の結果を図4~図6に示す。図1はそれぞれ生理食塩水点眼群(対照)、化合物1の0.4%溶液点眼群及び化合物1の0.8%溶液点眼群の代表的な撮影画像であるが、生理食塩水点眼群では網膜虚血領域(無灌流領域)及び新生血管領域が顕著に認められるのに対し、化合物1の0.4%及び0.8%溶液点眼群では、それぞれ抑制されていることが判る。図2及び図3は、網膜虚血領域(無灌流領域)及び新生血管領域を定量化した結果である。図2から、生理食塩水点眼群(N=14)の100%に対し、化合物1の0.4%溶液点眼群(N=12)及び化合物1の0.8%溶液点眼群(N=11)では77.0%及び58.1%と、無灌流領域が用量依存的且つ有意に抑制されたことが判明した。さらに図3から、生理食塩水点眼群の100%に対し、化合物1の0.4%溶液点眼群及び化合物1の0.8%溶液点眼群では58.2%及び52.7%と、新生血管領域が有意に抑制されたことが判明した。
脈絡膜血管新生モデルマウス(Mice CNV(choroidal neovascularization) Model)に対する効果
加齢黄斑変性等のモデルとして知られているMice CNV Modelにおける化合物1の有効性を調べるため、以下の方法に従って検討した。
A.試験に使用した薬剤及び動物
実施例1と同様に調整した化合物1溶液:0.4%溶液、0.8%溶液(点眼量:20μl)
実験動物: C57BL/6JJclマウス(6-10週齢、雄性、一群11~12匹)
CNVモデルの作成・評価は、文献(J. Leukoc. Biol. 2003;74:25-32、又はAm. J. Pathol. 1998;153:1641-1646、等)を参考に行った。すなわち、トロピカミド点眼にてマウスの瞳孔を散瞳した後、ケタラール100mg/Kgとセラクタール10mg/Kgを腹腔内投与し麻酔し、1眼につき4spotsの光凝固を行った。光凝固は、コンタクトレンズとしてカバーグラスを用いたスリットランプデリバリーシステムにより、クリプトンレーザー照射(75-μm spot size, 0.1 seconds duration, 200 mW)にて行った。群構成は、生理食塩水点眼群(対照)、化合物1の0.4%溶液点眼群及び化合物1の0.8%溶液点眼群であり、点眼は1日3回行った。光凝固処置当日をday 0とし、day 0からday 7まで点眼し、day 7にフラットマウントを作成、血管をFITC-レクチンで染色し評価した。具体的には、まず、出血や組織破壊の見られるspotは除外例とし、各採用例spotのCNV volumeをNIS-Elements AR Version 4.13にて計算後、一眼あたりの平均値(μm3)を算出した。
結果を図9に示す。対照群(Control)のCNV volumeが109177±26399μm3であるのに対し、化合物1の0.4%及び0.8%溶液点眼群では、それぞれ56408±9007μm3、88387±33678μm3と、脈絡膜血管新生が抑制されたことが判明した。
Kimbaマウスに対する効果
網膜血管新生を発症するVEGF遺伝子導入マウスとして知られているKimba(trVEGF029)マウスにおける化合物1の有効性を調べるため、以下の方法に従って検討した。
A.試験に使用した薬剤及び動物
実施例1と同様に調整した化合物1溶液:0.8%溶液(点眼量:20μl)
実験動物: Kimbaマウス(Lions Eye Institute Ltd.より購入、一群6匹)
同一日に出生したKimbaマウスに対し、生後1か月から生理食塩水(対照)又は化合物1の0.8%溶液を一日3回点眼し、2週間の点眼後、麻酔下にて蛍光眼底造影検査と光干渉断層計で評価した。具体的には、まず蛍光眼底造影検査では、トロピカミド点眼にてマウスの瞳孔を散瞳した後、ケタラール100mg/Kg及びセラクタール10mg/Kgの腹腔内投与にて麻酔し、次いで腹腔内にフルオレセイン蛍光眼底造影剤6μl/gを注入後、Heidelberg Retina Angiograph (HRA, Heidelberg, Germany)にて蛍光眼底造影検査を行った。また、光干渉断層計の評価では、トロピカミド点眼にてマウスの瞳孔を散瞳後、ケタラール100mg/Kg及びセラクタール10mg/Kgの腹腔内投与にて麻酔し、5Line 6mm lengthでX軸とY軸方向をThe Cirrus HD-OCT(Carl Zeiss Meditec, Dublin, CA)で撮影し、平均化最大網膜厚を計測(統計解析はStudent’s t検定)した。
結果を図10及び図11に示す。図10の上段は蛍光眼底造影、下段は光干渉断層計による各群の代表的な撮影画像である。なお、参考例として正常マウスの画像(左側、この例の最大網膜厚は276μm)を併せて示す。生理食塩水点眼では浮腫が認められ、網膜が肥厚しているのに対し、化合物1の0.8%溶液点眼では浮腫が抑制され、網膜厚も正常マウス程度であることが判る。図11は網膜厚の数値をグラフ化したものであるが、生理食塩水点眼群(対照)の平均化最大網膜厚が361.8±36.1μmであるのに対し、化合物1の0.8%溶液点眼群では、256.7±35.7μmと、網膜の肥厚が有意に抑制されたことが判明した。
タイトジャンクションに対する効果
細胞間バリアーに対する化合物1の有効性を調べるため、以下の方法に従って検討した。
常法に従い、マウス脳微小血管内皮細胞であるb-END3(bEND.3:ATCC CRL-2299(登録商標))を3.5cm Dishにて継代培養し(9×105cells/dish)、継代して6日目から試験を開始した。薬物処置条件は、無処置例(図中controlと表記する)、VEGF刺激例(25ng/ml、24時間:図中VEGF(25ng/ml 24hours) stimulationと表記する)、化合物1(3μM又は30μM)前処置(3時間)後VEGF刺激例(25ng/ml、24時間:図中VEGF + Compound 1(3μM 3hours) pretreatment又はVEGF + Compound 1(30μM 3hours) pretreatmentと表記する)、IL-6刺激例(10ng/ml、24時間:図中IL-6(10ng/ml 24hours) stimulationと表記する)及び化合物1(30μM)前処置(3時間)後IL-6刺激例(10ng/ml、24時間:図中IL-6 + Compound 1(30μM 3hours) pretreatmentと表記する)の計5例又は6例である。
試験後の細胞を、以下の手順により免疫染色し、クローディン-5(Claudin-5)又はFアクチン(F-Actin)の発現を評価した。すなわち、試験後の細胞を、常温で100%メタノールで5分処理し、さらに50%メタノールで5分処理して、PBSで洗浄(5分×2回)した。次いで、綿棒でカバーガラス大にトリミングし、Dakoペンで回りを囲み、10%正常ヤギ血清(10% normal goat serum ready-to-use(Invitrogen))にてブロッキング(30分、常温)して、4℃で、一夜放置した。ウサギ抗クローディン-5抗体(Rabbit anti-Claudin-5 (Invitrogen 34-1600))又はウサギ抗F-アクチン抗体(Rabbit anti-F-actin (Biossusa bs-1571R))の25倍希釈液を50~70μLを滴下した後、PBSで洗浄(10分×3回)して1次処理した。これを、常温で、遮光して60分静置して、Alexa Fluo488(登録商標)で標識した抗ウサギIgG FITC(Alexa Fluo488 anti-Rabbit IgG FITC)の200倍希釈で2次抗体処理した後、PBSで洗浄(10分×3回)した。DAPIで核を染色して、次いでクリスタルマウントでカバーガラスして、顕微鏡(×400倍)で撮影した。クローディング-5についての結果を図12に示し、F-アクチンについての結果を図13に示す。
Claudin-5の免疫染色結果を図12に、F-Actinの免疫染色結果を図13に示す。図12から明らかなように、VEGF又はIL-6刺激により低下するClaudin-5の発現が、化合物1の前処置により改善していることがわかる。また、図13から明らかなように、VEGF又はIL-6刺激により生じるF-Actinの重合が、化合物1の前処置により抑制されていることがわかる。従って、化合物1は細胞間バリアーの破綻に対する抑止効果が期待できることが判明した。
Claims (15)
- (S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を有効成分とする眼底疾患の予防又は治療剤。
- 眼底疾患が糖尿病網膜症である請求項1の予防又は治療剤。
- 眼底疾患が糖尿病黄斑浮腫である請求項1の予防又は治療剤。
- 眼底疾患が加齢黄斑変性である請求項1の予防又は治療剤。
- 点眼剤である請求項1~4の予防又は治療剤。
- (S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物並びに薬学的に許容される担体を含有してなる眼底疾患予防又は治療のための医薬組成物。
- 眼底疾患が糖尿病網膜症である請求項6の医薬組成物。
- 眼底疾患が糖尿病黄斑浮腫である請求項6の医薬組成物。
- 眼底疾患が加齢黄斑変性である請求項6の医薬組成物。
- 点眼剤である請求項6~9の医薬組成物。
- (S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物、及び点眼薬に許容される担体を含有してなる点眼薬。
- (S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする眼底疾患の予防又は治療方法。
- 投与が、点眼による投与である、請求項12に記載の方法。
- 眼底疾患の予防又は治療剤を製造するための、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物の使用。
- 眼底疾患の予防又は治療剤が、点眼薬である、請求項14に記載の使用。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14788679.0A EP2990040B1 (en) | 2013-04-24 | 2014-03-03 | Therapeutic agent for eyeground disease |
EP19199248.6A EP3626245B1 (en) | 2013-04-24 | 2014-03-03 | Therapeutic agent for eyeground disease |
KR1020157026982A KR102177199B1 (ko) | 2013-04-24 | 2014-03-03 | 안저질환 치료제 |
CN201480013090.6A CN105050600B (zh) | 2013-04-24 | 2014-03-03 | 眼底疾病治疗剂 |
US14/362,850 US20160339018A1 (en) | 2013-04-24 | 2014-03-03 | Therapeutic agent for ocular fundus disease |
US14/481,467 US20140378441A1 (en) | 2013-04-24 | 2014-09-09 | Therapeutic agent for ocular fundus disease |
HK16102561.7A HK1214526A1 (zh) | 2013-04-24 | 2016-03-07 | 眼底疾病治療劑 |
US15/387,113 US10426783B2 (en) | 2013-04-24 | 2016-12-21 | Therapeutic agent for ocular fundus disease |
US16/542,461 US20190365776A1 (en) | 2013-04-24 | 2019-08-16 | Therapeutic agent for ocular fundus disease |
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US14/362,850 A-371-Of-International US20160339018A1 (en) | 2013-04-24 | 2014-03-03 | Therapeutic agent for ocular fundus disease |
US14/481,467 Division US20140378441A1 (en) | 2013-04-24 | 2014-09-09 | Therapeutic agent for ocular fundus disease |
US15/387,113 Continuation US10426783B2 (en) | 2013-04-24 | 2016-12-21 | Therapeutic agent for ocular fundus disease |
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WO2014174747A1 true WO2014174747A1 (ja) | 2014-10-30 |
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EP (2) | EP2990040B1 (ja) |
JP (1) | JP5557408B1 (ja) |
KR (1) | KR102177199B1 (ja) |
CN (1) | CN105050600B (ja) |
HK (1) | HK1214526A1 (ja) |
TW (1) | TWI629985B (ja) |
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JP2015229671A (ja) * | 2014-06-06 | 2015-12-21 | 株式会社デ・ウエスタン・セラピテクス研究所 | 網膜色素上皮細胞保護剤 |
CN106604730B (zh) | 2014-09-24 | 2019-12-20 | 兴和株式会社 | 角膜厚度调节剂 |
US10376523B2 (en) | 2014-09-25 | 2019-08-13 | Kowa Company, Ltd. | Aqueous composition containing ripasudil, or a salt, or a solvate thereof |
JP6244038B2 (ja) * | 2014-09-25 | 2017-12-06 | 興和株式会社 | 医薬製剤 |
JP2016135780A (ja) * | 2015-01-16 | 2016-07-28 | 興和株式会社 | 水性組成物 |
KR20160108121A (ko) | 2015-03-06 | 2016-09-19 | 코와 가부시키가이샤 | 수성 조성물 |
US20180296474A1 (en) * | 2015-10-13 | 2018-10-18 | INSERM (Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion |
EP4088719A1 (en) * | 2015-10-13 | 2022-11-16 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion |
JP6928479B2 (ja) | 2017-05-12 | 2021-09-01 | 学校法人順天堂 | 拒絶反応抑制剤 |
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Also Published As
Publication number | Publication date |
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EP2990040A1 (en) | 2016-03-02 |
EP3626245B1 (en) | 2021-05-05 |
US20160339018A1 (en) | 2016-11-24 |
US20170100409A1 (en) | 2017-04-13 |
EP2990040B1 (en) | 2019-12-04 |
KR102177199B1 (ko) | 2020-11-10 |
TW201440774A (zh) | 2014-11-01 |
HK1214526A1 (zh) | 2016-07-29 |
EP3626245A1 (en) | 2020-03-25 |
US20140378441A1 (en) | 2014-12-25 |
CN105050600B (zh) | 2018-09-28 |
CN105050600A (zh) | 2015-11-11 |
US10426783B2 (en) | 2019-10-01 |
JP5557408B1 (ja) | 2014-07-23 |
TWI629985B (zh) | 2018-07-21 |
KR20150145229A (ko) | 2015-12-29 |
JP2014224090A (ja) | 2014-12-04 |
US20190365776A1 (en) | 2019-12-05 |
EP2990040A4 (en) | 2017-07-05 |
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