JP2015027980A - Eye drop therapeutic agent for eye disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an effective therapeutic agent for eye disease, particularly, eye disease associated with angiogenesis, macular hole, macular membrane, visual impairment, vitreous opacity or fundal hemorrhage, or decrease in retinal sensitivity, and eye fatigue.SOLUTION: An eye drop therapeutic agent for eye disease comprises phytoalexin such as transresveratrol included in cyclodextrin for solubilization.

Description

  The present invention is an ophthalmic treatment for ophthalmic diseases, particularly ocular diseases associated with neovascularization, macular hole, macular membrane, visual impairment, vitreous opacification or fundus hemorrhage, or a decrease in retinal sensitivity, instillation of eye strain It relates to therapeutic drugs.

  With the aging society, various eye diseases, in particular macular hole, epimacular membrane, vitreous opacification or fundus hemorrhage, have become a problem. In addition, corneal neovascularization due to unexplained visual impairment and excessive use of contact lenses is also increasing.

  As a treatment method for retinopathy of prematurity, a treatment in which an anti-VEGF antibody is locally administered has been studied. However, according to this method, the administered anti-VEGF antibody is transferred to the whole body, resulting in an adverse effect on the whole body. It is inappropriate for the treatment of retinopathy of prematurity.

  At present, these diseases have a problem that there is no effective treatment, or there is no choice but to perform treatment at the stage where visual acuity has deteriorated, resulting in an increase in medical costs and patient pain.

  If an effective treatment for the above problems is provided, and treatment can be performed with eye drops when the eyesight is good at the onset of illness, the social life of the patient becomes fun and light. The development of such eye drops is urgent.

This invention solves said subject and is as follows.
(1) An ophthalmic treatment for ophthalmic diseases containing phytoalexin which has been included and solubilized with cyclodextrin;
(2) The eye drop treatment according to (1), wherein the phytoalexin concentration in the eye drop treatment is 0.01 to 0.1% by weight;
(3) The ophthalmic therapeutic agent according to (1) or (2), wherein the inclusion weight ratio of cyclodextrin: phytoalexin is 1: 1 to 10;
(4) The eye drop treatment according to any one of (1) to (3), wherein the phytoalexin is a transstilbenoid;
(5) The ophthalmic therapeutic agent according to (4), wherein the transstilbenoid is transresveratrol;
(6) The ophthalmic therapeutic agent according to any one of (1) to (5), wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin;
(7) The eye disease is an ocular disease associated with angiogenesis, macular hole, epimacular membrane, visual impairment, vitreous opacification or fundus hemorrhage, or decreased retinal sensitivity, eye strain (1) to (6) ) The ophthalmic therapeutic agent according to any one of
(8) Retinopathy of prematurity, macular degeneration, diabetic retinopathy, angle angiogenesis, SLE, central choroidal disease, central retinal vein occlusion, arteriosclerosis, angiogenesis (7) Eye drops for glaucoma, internal carotid artery occlusion, papillary neovascularization, iris rubeosis, or corneal neovascularization.

  According to the present invention, it is possible to effectively treat various eye diseases, particularly eye diseases associated with angiogenesis, decreased retinal sensitivity, and eye strain, retinal macular hole or epithelium, visual impairment, vitreous opacity or Can treat fundus hemorrhage when the eyesight is good at the beginning

It is a figure which shows the relationship between the elapsed time after instillation of the eye drop therapeutic agent of this invention, and the thickness of a crystalline lens. It is a figure which shows the relationship between the cyclodextrin inclusion trans resveratrol density | concentration in an eye drop treatment, and the maximum lens thickness change rate after instillation. It is the photograph of the eye part at the time of instilling before and after ultraviolet irradiation. Negative Control means that PBS is instilled before and after UV irradiation, Post eyedrops are PBS before UV irradiation, and eye drops are instilled after UV irradiation. Pre Post eyedrops are instilled before and after UV irradiation. The case where a therapeutic agent is instilled is shown. It is a figure which shows the retinal sensitivity before and behind the eye drop of the eye drop therapeutic agent of this invention.

  The ophthalmic therapeutic agent of the present invention contains phytoalexin that has been included and solubilized with cyclodextrin.

  The phytoalexin in the present invention causes calcium influx (inward flow) when plant cells are subjected to elicitor stimulation such as ultraviolet rays, trauma, virus or bacterial infection, and the cells subjected to elicitor stimulation are killed. However, it means a protective substance that is biosynthesized to protect other cells from elicitor stimulation, and known substances can be used, but those that are sparingly soluble or insoluble in water are preferred. Examples of phytoalexins include polyphenol derivatives such as flavonoids, terpenoids, curcumin, transstilbenoids, ellagic acid, and tannin, and fatty acid derivatives. As the phytoalexin, trans stilbenoid is preferable.

  Examples of transstilbenoids include piceatannol, pinosylvin, pterostilbene, transresveratrols, α-viniferin, and gnetin, and transresveratrols are preferred. Transresveratrols include transresveratrol, ie, 3,3 ', 5-trihydroxy-trans-stilbene and its derivatives. Transresveratrol derivatives include transresveratrol dimers, esters of transresveratrol, ethers or salts, esters of transresveratrol dimers, ethers or salts, and the like. Also includes derivatives that are converted to trol.

  Other specific examples of phytoalexins include fomilactone, sakuranetin, ferulic acid, coumaric acid, oryzalexin, rubimine, sorativibone, phytocasan, pisatine, 6-methoxybenzoxazoline, 6,7-dimethoxycoumarin, capsidiol, phenyl Phenarenone, glyceolin, betablegullin, lysine, 6-methoxymelein, brassin, ricitin, butyne, luteolin, quercetin, α-viniferin, capsidiol, rhamnetin, isoquitigenin, phystine, tetrahydroxyflavone, pentahydroxyflavone Etc.

  As the cyclodextrin in the present invention, any cyclodextrin and derivatives thereof can be used as long as transresveratrol is included and solubilized. Preferred cyclodextrins are α-cyclodextrin and derivatives thereof, β-cyclodextrin derivatives, γ-cyclodextrin and derivatives thereof, and δ-cyclodextrin and derivatives thereof. Examples of the cyclodextrin derivative include hydroxyalkylated cyclodextrin, sulfonylcyclodextrin, and sulfobutyletherified cyclodextrin, and hydroxyethylcyclodextrin, hydroxypropylcyclodextrin, sulfonyl-β-cyclodextrin, sulfone are particularly preferable. Butyl ether-β-cyclodextrin, among which 2-hydroxypropyl-β-cyclodextrin is particularly preferred.

  In the present invention, the inclusion ratio (weight ratio) of phytoalexin: cyclodextrin such as transresveratrol is preferably 1: 1 to 20, more preferably 1: 1 to 10, particularly preferably 1: 1 to 1. 5.

  In the present invention, the concentration of phytoalexin such as transresveratrol is preferably 0.01 to 0.1% by weight, particularly preferably 0.01 to 0.05% by weight.

  The present invention may include a physiologically active substance other than phytoalexin.

  In the present invention, inclusion and solubilization of phytoalexin such as transresveratrol with cyclodextrin can be performed by a conventional method.

  The ophthalmic therapeutic agent of the present invention is used for the prevention or treatment of eye diseases, particularly ocular diseases associated with angiogenesis, macular hole, macular membrane, visual impairment, vitreous opacification, and fundus hemorrhage. Furthermore, the eye drop treatment of the present invention is a drug for reducing retinal sensitivity and improving eye strain.

In the present invention, the wearing feeling of the eye drops is good, and phytoalexins such as transresveratrol are transferred into the eye and treatment of retinal diseases is possible.
In the present invention, as the intraocular transfer is improved, the direct action of phytoalexin has a function of preventing the inflow of calcium into the smooth muscle, dilating blood vessels, improving blood flow, It has the effect of relaxing and relaxing the tension of the body muscles and thinning the lens, and prevents the inflow of calcium into the platelets, making it difficult to coagulate blood and enhancing the effect of improving blood flow. Also, as an indirect action, it activates HDAC (histone deacetylase) to prevent histone acetylation, condenses chromatin structure, and suppresses the production of cytokines, VEGF, interleukins, TNF, etc., which are harmful to the living body. The action to enhance is also enhanced.

According to the present invention, since the action of inhibiting the production of VEGF is enhanced by activation of HDAC in the eye, ocular diseases associated with angiogenesis, such as retinopathy of prematurity, macular degeneration, diabetic retina , Angle angiogenesis, SLE, central retina choroidosis, central retinal vein occlusion, arteriosclerosis, neovascular glaucoma, internal carotid artery occlusion, papillary neovascularization, iris rubeosis, excessive use of contact lenses and cornea It is effective for the prevention and treatment of corneal neovascularization at the time of ulcer and corneal neovascularization by ultraviolet rays or strong light.
The present invention is an ozone hole, so when going to a place where the obstacle of ultraviolet rays becomes strong, going to sea bathing, climbing to a high snowy mountain or going to ski, when an airplane pilot flies at high altitude (a pilot in the 40s) When astronauts go to space, they can protect their eyes and prevent and treat eye diseases when they go to space (especially for Westerners with little pigment on the iris or fundus of their eyes) It is valid).

Since the present invention improves the retinal sensitivity of a patient whose retinal sensitivity has decreased, it can be used as a retinal sensitivity improving agent.
The present invention further includes a skin disease spray treatment solution containing phytoalexin that is clathrated and solubilized with cyclodextrin, and the occurrence of skin disease can be prevented by spraying this solution onto the skin.

Example 1: Trial to verify the direct action (change in lens thickness) of transresveratrol (Preparation of eye drops)
Transresveratrol (manufactured by Wako Pure Chemical Industries) was selected as the phytoalexin, and 2-hydroxypropyl-β-cyclodextrin (manufactured by SiGMA) was selected as the cyclodextrin surrounding the phytoalexin, and the following eye drops were prepared.
<Eye drops 1>
0.05% by weight of 2-hydroxypropyl-β-cyclodextrin is dissolved in distilled water, 0.005% by weight of transresveratrol is added to this solution, and a transparent solution is obtained by inclusion. Eye drop treatment 1 was placed in a blue colored 5 ml eye drop bottle to prevent light.
<Eye drops 2>
Dissolve 0.1% by weight of 2-hydroxypropyl-β-cyclodextrin in distilled water, add 0.01% by weight of transresveratrol to this solution, and encapsulate to obtain a transparent solution. An eye drop treatment 2 was placed in a blue colored 5 ml eye drop bottle to prevent light.
<Eye drops 3>
Dissolve 0.2% by weight of 2-hydroxypropyl-β-cyclodextrin in distilled water, add 0.02% by weight of transresveratrol to this solution, and encapsulate to obtain a transparent solution. An eye drop treatment 3 was placed in a blue colored 5 ml eye drop bottle to prevent light.

(Measurement of lens thickness change)
One of the eye drop treatment drugs 1 to 3 was instilled once into the right eye of a 30-year-old female volunteer who was the subject, and the thickness of the lens after instillation was measured over time. Three measurements were taken at one week intervals. The change in the thickness of the crystalline lens was measured using ultrasonic waves with a Nidec ECHOSCAN US-1800. The measurement results are shown in FIG. 1, and the following can be understood from FIG.
The first measurement was when instillation medicine 1 was instilled, and the thickness of the lens after instillation was almost unchanged.
The second measurement after one week was when instillation treatment 2 was instilled, and the lens thickness after instillation began to thin over time, and the value after about 1 hour was the thinnest at 3.43 mm. .
Further, the third measurement after one week is when instillation treatment 3 is instilled, and the effect of reducing the thickness of the crystalline lens after instillation is stronger than that of instillation treatment 2, and the value after about 1 hour 30 minutes is The thinnest was 3.3 mm.
From these results, transresveratrol, which has been solubilized and solubilized, can be transferred into the organ (in the eyeball) by instillation to relax and relax the ciliary muscles, thereby reducing the thickness of the lens. I understood.
FIG. 2 is a graph obtained by processing the data of FIG. 1 to obtain the maximum lens thickness change rate (maximum value of thinning)% and graph this by the concentration of transresveratrol. As can be seen from FIG. 2, the thickness of the lens decreases depending on the concentration of transresveratrol. From this, it was proved that transresveratrol encapsulated with cyclodextrin entered the eye and exerted a pharmacological effect.

  When the ciliary body relaxes, the uneven and partial unbalanced tension of the ciliary body is corrected, the irregular shape of the lens becomes uniform and ideal, the lens astigmatism due to lens distortion is improved, The light beam waist is thin and ideal, increasing the contrast sensitivity. In addition, the depth of focus becomes deeper, the near vision is improved, the far vision is improved, the distance is easily focused, the stereoscopic effect is improved, the appearance quality is improved, and the eye strain is also improved.

Example 2: Experiment for verifying indirect action of transresveratrol in ultraviolet irradiation (ultraviolet irradiation)
Each morning from 7 to 8 o'clock in the morning, the mouse eyes were irradiated with intense ultraviolet light (UVA 100 μw + UVB 100 μw (100 μw × 1 hour = 0.36 J)), and this was repeated for one week. Mature mice were divided into 3 groups of 5 mice, and experiments were conducted with 10 eyes.

(Eye drops for eye drops)
Before and after the ultraviolet irradiation, eye drops 2 and PBS were instilled into 3 groups of mice as follows.
In the first group, as a negative control, 1 drop of PBS was applied at 6 o'clock 1 hour before UV irradiation, 1 hour of UV irradiation was applied at 7-8 o'clock, and 1 drop of PBS was applied at 9 o'clock 1 hour later. PBS instillation was performed at each time of hour, 16:00, 20:00 and 24:00.
The second group is a Post eye drop. First, 1 drop of PBS is applied at 6 o'clock 1 hour before UV irradiation, UV light is applied for 1 hour from 7 o'clock to 8 o'clock, and 1 hour after that, 1 drop of eye drop treatment 2 is applied. After instillation, one drop of eye drop treatment 2 was instilled at each time of 12:00, 16:00, 20:00, and 24:00.
The third group is pre-post-instillation, one drop of eye drop 2 is applied 1 hour before UV irradiation (6 o'clock), UV irradiation is applied for 1 hour at 7-8 o'clock, and 1 hour later, at 9 o'clock. One drop of medicine 2 was instilled, and then one drop of instillation medicine 2 was instilled at 12:00, 16:00, 20:00, and 24:00.

(result)
The effect of instillation is shown in FIG. The following can be seen from FIG.
In Negative Control, in which only PBS is instilled before and after UV irradiation, many corneal neovascularizations are proliferating in the cornea because VEGF is produced and secreted. Strong swelling and ulceration are seen in the eyelid skin, which is due to the production of interleukin, TNF, etc., which are harmful to the living body.
In Post-instillation, in which PBS is applied before UV irradiation, and ophthalmic treatment 2 is applied after UV irradiation, corneal neovascularization in the cornea is clearly decreased, swelling of the eyelid skin is mild, and ulcers are also present. It disappeared and a therapeutic effect was recognized.
In Pre Post eye drop, which is a case where the eye drop treatment 2 is instilled before and after the irradiation of ultraviolet rays, the corneal neovascularization on the cornea has disappeared. This was considered to be a result of suppression of VEGF production and secretion. Also, there was no swelling or ulceration of the eyelids. This was thought to be the result of activation of HDAC (histone deacetylase) by the eye-drop treatment, condensation of the chromatin structure, and suppression of the production of cytokines, VEGF, interleukins, TNF, and the like harmful to the living body. It was proved that trans-resveratrol encapsulated with cyclodextrin has preventive and therapeutic effects on lesions.

When trans-resveratrol is included with cyclodextrin, as can be seen from Example 1, trans-resveratrol, which does not easily move into the organ (intraocular), can be easily transferred into the organ. It is thought that the pharmacological effect is exhibited in the eye because it is relaxed and the lens is thinned.
In addition, when trans-resveratrol is included in cyclodextrin, as can be seen from Example 2, the stability of the drug is protected, structural change (cisification) is reduced, pharmacological effects are exerted, and HDAC (histone deacetylase) is exhibited. ) To condense the chromatin structure and suppress the production of cytokines, VEGF, interleukins, TNF, etc., which are harmful to the living body and cause diseases, and are thought to suppress angiogenesis, and inflammation and ulcers Suppress. In the present invention, it has been found that transresveratrol is useful for the prevention and treatment of various intraocular and extraocular diseases.

Example 3 Preparation of Eye Drops 0.1% by weight of 2-hydroxypropyl-β-cyclodextrin (manufactured by Sigma) was dissolved in distilled water and 0.01% by weight of transresveratrol ( Wako Pure Chemical Industries, Ltd.) is added, transresveratrol is clathrated with 2-hydroxypropyl-β-cyclodextrin to obtain a transparent solution, and this is put into a blue-colored 5 ml ophthalmic bottle that prevents ultraviolet rays and light. The therapeutic agent was prepared.

Example 4: Treatment Example 1
The patient is a 75-year-old man whose left eye is diagnosed with the epimacular membrane and has visual acuity:
Vs = 0.1 (0.4 × + 2.5D = cyl−0.75DA × 165 °)
The vision decreased.
When this patient was continuously instilled three times per day with the eye drop preparation prepared in Example 3, the visual acuity was 1 month and 20 days later:
Vs = 0.15 (0.7 × + 2.5D = cyl−1.25DA × 155 °)
And improved. In addition, the growth of the epimacular membrane stopped and decreased.
After further administration of eye drops, eyesight after 1 year and 3 months:
Vs = 0.2 (1.0 × + 2.75D = cyl−0.50DA × 10 °)
And further improved. In addition, the epimacular membrane almost disappeared.
What was corrected visual acuity 0.4 improved to corrected visual acuity 1.0 and was judged to be effective.

Example 5: Treatment example 2
The patient is a 66-year-old woman whose right eye is diagnosed with a macular hole and has visual acuity:
Vd = 0.3 (0.8 × −4.0D = cyl−1.0 DA × 70 °)
There was a slight decrease in corrected visual acuity.
When this patient was administered the eye drop preparation prepared in Example 3 in the same manner as in Example 4, three months later, the visual acuity:
Vd = 0.4 (0.9 × −5.0D = cyl−1.5DA × 75 °)
And improved slightly.
After further administration of eye drops, vision acuity after 7 months:
Vd = 0.5 (1.0 × −6.0D = cyl−0.5DA × 180 °)
And vision improved. The macular hole also healed.

Example 6: Treatment example 3
The patient is a 63-year-old woman with a mild macular hole and mild epithelial membrane in her left eye,
Pre-treatment vision:
Vs = 0.06 (0.4 × −4.5D = cyl−1.5DA × 150 °)
Met.
When this patient was continuously instilled three times per day with the eye drop preparation prepared in Example 3, the visual acuity one week later:
Vs = 0.07 (corrected visual acuity 0.6)
Improved after 2 months
Vs = 0.05 (corrected visual acuity 0.7)
Improved after 4 months:
Vs = 0.07 (corrected visual acuity 0.8)
Improved. During this ophthalmic administration, the macular hole and the epimacular membrane gradually decreased.
Visual acuity after instillation after 6 months:
Vs = 0.08 (1.2 × −5.0D = cyl−0.75DA × 165 °)
As a result, the macular hole and the epimacular membrane disappeared and healed.
Corrected visual acuity improved from 0.4 to 1.2 in 6 months and judged to be effective.

Example 7: Treatment example 4
The patient is a 7-year-old man with poor naked eye vision, poor correction vision, poor diagnosis and suspected amblyopia.
Right Vd = 0.6 (0.7 × −0.25D = cyl−3.0DA × 180 °)
Left Vs = 0.7 (0.7 × −0.25D = cyl−3.0DA × 5 °)
Met.
When this patient was continuously instilled twice per day with the eye drops prepared in Example 3, the corrected visual acuity in 4 months:
Vd = 0.8 (1.5 × −0.50D = cyl−3.5DA × 5 °)
Vs = 0.7 (1.2 × −0.50D = cyl−3.0DA × 5 °)
There was an improvement.
Thereafter, 0.02% by weight of transresveratrol prepared by inclusion in 0.1% by weight of 2-hydroxypropyl-β-cyclodextrin was prepared in the same manner as in Example 3 except that the concentration of each component was changed. As a result, the naked eyesight and the corrected eyesight improved to 1.2 after 3 months, and it was judged to be effective.
Vd = 1.2 (nc)
Vs = 1.2 (nc)

Example 8: Treatment example 5
The patient is a 62 year old male diagnosed with vitreous opacification and fundus bleed.
When this patient was continuously instilled with the ophthalmic preparation prepared in Example 3 three times per day, vitreous opacification was almost eliminated by treatment for 4 months, and vitreous opacification and fundus hemorrhage were caused by treatment for 8 months. Disappeared.

Example 9: Treatment Example 6
The patient is a 73-year-old male with octopus static perimeter having reduced retinal sensitivity in the left eye and eye strain.
This patient was instilled with the eye drop preparation prepared in Example 3 three times a day for 17 days. The measurement results before and after instillation are shown in FIG. According to this, the drop in retinal sensitivity is improved by eye drops, and the eye strain is also improved.

  According to the present invention, an ophthalmic treatment capable of effectively treating ocular diseases associated with angiogenesis such as retinopathy of prematurity, decreased retinal sensitivity, and eye strain, or a macular hole or a macular hole in the retina, visual impairment In addition, it is possible to provide an eye drop treatment agent capable of treating vitreous opacification or fundus hemorrhage at a stage of good visual acuity at the initial stage of its onset.

Claims (8)

  An ophthalmic treatment for ophthalmic diseases containing phytoalexin that has been solubilized by inclusion with cyclodextrin.   The eye drop treatment according to claim 1, wherein the phytoalexin concentration in the eye drop treatment is 0.01 to 0.1% by weight.   The ophthalmic treatment according to claim 1 or 2, wherein the inclusion weight ratio of cyclodextrin: phytoalexin is 1: 1 to 10.   The ophthalmic therapeutic agent according to any one of claims 1 to 3, wherein the phytoalexin is a transstilbenoid.   The eye drop treatment according to claim 4, wherein the transstilbenoid is transresveratrol.   The ophthalmic treatment according to any one of claims 1 to 5, wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.   The eye disease is an ocular disease accompanied by neovascularization, macular hole, epimacular membrane, visual impairment, vitreous opacification or fundus hemorrhage, decreased retinal sensitivity, or eye strain. The eye drop treatment described in the item.   Retinopathy of prematurity, macular degeneration, diabetic retinopathy, angle angiogenesis, SLE, central choroidal disease, central retinal vein occlusion, arteriosclerosis, neovascular glaucoma, internal The ophthalmic treatment according to claim 7, which is carotid artery occlusion, papillary neovascularization, iris rubeosis, or corneal neovascularization.