KR20220079480A - Pharmaceutical composition comprising sglt-2 inhibitor for preventing or treating diabetic opthalmopathy disease - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating diabetic eye disease, including a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, and a method for preventing or treating diabetic eye disease using the same.

Description

Pharmaceutical composition for preventing or treating diabetic eye disease comprising a SGLT-2 inhibitor {PHARMACEUTICAL COMPOSITION COMPRISING SGLT-2 INHIBITOR FOR PREVENTING OR TREATING DIABETIC OPTHALMOPATHY DISEASE}

The present invention relates to a pharmaceutical composition for preventing or treating diabetic eye disease, including a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, and a method for preventing or treating diabetic eye disease using the same.

The rate of blindness due to diabetes and the accompanying diabetic eye disease is increasing due to western eating habits and the like, and the medical cost burden is increasing accordingly.

Diabetic retinopathy (DR), one of the diabetic eye diseases, is the most common microvascular complex and the main cause of visual impairment in diabetic patients and working-age populations. As diabetic retinopathy progresses, although neovascularization causes serious visual impairment in the late stages of diabetic retinopathy, macular edema due to vascular leakage may occur at any stage of diabetic retinopathy and may impair visual acuity.

In particular, diabetic retinopathy is the most common cause of blindness in diabetic patients, and is the world's third largest risk of blindness. It is also considered a disease.

In the case of such diabetic eye disease, the risk of blindness is very high, and although the treatment effect is high, there is a feeling of objection to the patient due to the nature of the treatment administered to the eye.

Anastasios Tentolouris et al., Int. J. Environ. Res. Public Health 2019, 16, 2965, 「SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects」

An object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetic eye disease, comprising a SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preventing or treating diabetic eye disease, comprising administering the pharmaceutical composition to a subject.

One aspect of the present invention for achieving the above object relates to a pharmaceutical composition for preventing or treating diabetic eye disease, comprising a SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

In the present invention, the “cotransporter 2) inhibitor” inhibits glucose reabsorption by inhibiting SGLT-2 in the renal proximal tubule.

Specifically, the SGLT-2 inhibitor may be inavogliflozin, but is not limited thereto.

In addition, specifically, the inavogliflozin may be represented by the following formula (1).

[Formula 1]

In the present invention, "diabetic eye disease" refers to any type of eye disease caused by diabetes, and generally the blood vessels supplying nutrients to the retina located at the back of the eye are weakened, and waste products are accumulated or bleeding occurs. Specifically, the diabetic eye disease may be one or more selected from the group consisting of diabetic retinopathy, macular edema, cataract, glaucoma, and paralytic strabismus, but is not limited thereto. Any eye disease that occurred as one of the complications can be included.

Diabetes mellitus is a metabolic disease that causes lesions in microvessels. If hyperglycemia continues due to diabetes, the capillaries of the retina in the eye are destroyed and new blood vessels are created. Due to this, a disease in which the optic nerve function is deteriorated due to insufficient nutrient supply to the eye is diabetic retinopathy, and the diabetic retinopathy includes both non-proliferative retinopathy and proliferative retinopathy.

The 'macular edema' is a disease in which edema occurs in the macula in the center of the retina. When blood vessels in the macula are blocked due to diabetes, new blood vessels are formed, and water or blood leaks into these weak vessels, causing stagnant macular edema.

The 'glaucoma' is a disease that causes an abnormality in the optic nerve due to various risk factors such as an increase in the constant pressure (intraocular pressure) maintained inside the eyeball, and when left unattended, the field of view gradually narrows and leads to blindness. It is known that glaucoma occurs three times more often in diabetic patients than in normal people, and the increase in intraocular pressure, which is the most important factor in glaucoma, to 21 mmHg or more was reported to be twice as high in diabetic patients than in normal people.

The 'cataract' is a disease in which the identity becomes cloudy and loses transparency. Diabetes is five times more likely to develop cataracts than normal, showing cataract findings in about 13% of all patients. The age of onset of cataracts is also known to appear relatively early in diabetic patients.

The 'paralytic strabismus' refers to strabismus caused by a problem in the process of transmitting electrical signals from the brain to the muscles that move the eyeball. Diabetes patients account for 36 to 42% of patients with paralysis, and the frequency of paralysis is 6 times higher in diabetic patients than in non-diabetic patients. In the case of diabetic patients, various abnormal metabolic processes are promoted due to high blood sugar, and in this process, harmful substances such as reactive oxygen species and final glycation products accumulate, causing nerve and blood vessel damage. Due to such blood vessel damage, the blood supply to the nerves that control the muscles that move the eyeball is lowered, which makes the nutrition supply difficult, and the nerve damage is accelerated due to the hypoxia.

In addition, specifically, the composition may be administered parenterally, specifically, it may be administered to the eye. In particular, it may be in the form of an eye drop for eye drop administration.

In one embodiment of the present invention, a composition containing a SGLT-2 inhibitor was administered as an eye drop, and unlike other administration routes, a high drug concentration level appeared in the vitreous, retina, and choroid, and excellent therapeutic effect for diabetic eye disease. confirmed that. In particular, unlike the conventional treatment for eye diseases administered through injection into the vitreous body, the composition of the present invention can be effectively applied to the treatment of eye diseases as it is conveniently administered to the eye as an eye drop and has the effect of greatly increasing the convenience of administration.

In addition, specifically, the composition may be one that further comprises an anti-VEGF (Vascular endothelial growth factor) antibody or a substance that binds to VEGF and inhibits the action of VEGF.

Vascular endothelial growth factor (VEGF) is an angiogenic factor that induces endothelial cell proliferation, is involved in the regeneration of damaged blood vessels, increases vascular permeability in tumor development, and plays an important role in angiogenesis. In particular, VEGF is known to be closely related to eye diseases such as diabetic retinopathy, macular degeneration, and macular edema. Anti-VEGF drugs are being administered to macular degeneration, retinal diseases, etc. as research results have been reported that angiogenesis can be inhibited in the retina when a factor antagonizing VEGF is injected.

The anti-VEGF antibody may be ranibizumab (Ranibizumab), or bevacizumab (Bevacizumab), but is not limited thereto, and any antibody antagonizing VEGF may be combined or combined with the composition of the present invention.

The form of the substance that binds to VEGF and inhibits the action of VEGF is not limited. For example, Aflibercept may be used in combination or combination with the composition of the present invention.

In one embodiment of the present invention, when the eye drop composition of the present invention and ranibizumab are co-administered, a therapeutic effect similar to that obtained by administering a high content of the SGLT-2 inhibitor even if the high content of the SGLT-2 inhibitor is not included It was confirmed that it can represent . Through this, it is possible to control the content of the SGLT-2 inhibitor by combining or combining with an anti-VEGF antibody or a substance that binds to VEGF and inhibits the action of VEGF.

In the present invention, “prevention” means any action in which the composition of the present invention delays the occurrence of diabetic eye disease.

In the present invention, “treatment” means any action that allows the composition of the present invention to improve or benefit symptoms of diabetic eye disease.

The pharmaceutical composition of the present invention may be applied in a pharmaceutically effective amount, and "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level The patient's gender, age, disease type, severity, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well-known in the medical field can be determined according to

Another aspect of the present invention relates to a method for preventing or treating diabetic eye disease, comprising administering the pharmaceutical composition to a subject.

The "individual" of the present invention includes an animal or human having diabetic eye disease whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention. The 'diabetic eye disease' is the same as described above.

In addition, specifically, the method for preventing or treating diabetic eye disease may include administering together an anti-VEGF antibody or a substance that binds to VEGF and inhibits the action of VEGF. 'Anti-VEGF antibody or a substance that binds to VEGF and inhibits the action of VEGF' is as described above.

By administering the composition for treatment according to the present invention to an individual, it is possible to effectively prevent and treat diabetic eye disease.

"Administration" of the present invention means introducing a predetermined substance into a human or animal by any suitable method, and the administration route of the therapeutic composition according to the present invention is orally through any general route as long as it can reach the target tissue. or parenterally. In addition, the therapeutic composition according to the present invention may be administered by any device capable of moving the active ingredient to the target cell.

The preferred dosage of the pharmaceutical composition according to the present invention varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition comprising the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof of the present invention maintains a high drug concentration in the vitreous, retina, and choroid when administered by eye drops, thereby exhibiting an excellent therapeutic effect on diabetic eye disease. . Furthermore, even when a low content of SGLT-2 inhibitor was contained, despite the extremely limited blood exposure of the drug, it was confirmed that the drug exhibited excellent drug efficacy only through exposure to the retina and choroid. As shown, it is very effective in treating eye diseases. In particular, unlike conventional therapeutic agents administered through injection into the vitreous body, it is conveniently administered to the eye as an eye drop and has the effect of greatly increasing the convenience of administration.

It should be understood that the effects of the present invention are not limited to the above-described effects, and include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

1 shows the results of measuring the fluorescence intensity on the 21st day after administration of the composition of the present invention.
Figure 2 shows the fundus photograph of the 21st day after administration of the composition of the present invention.
3 shows the results of measuring drug concentrations in plasma, vitreous, retina and choroid based on each test substance group at 1, 4, 8, 16 and 24 hours after administration of the composition of the present invention.
4 shows the results of measuring the drug concentration of each test substance group in samples (plasma, vitreous, retina and choroid) at 1, 4, 8, 16 and 24 hours after administration of the composition of the present invention.
5 shows the results of measuring the fluorescence intensity on the 21st day after administration of each composition in which the content of inavogliflozin is different and ranibizumab combined administration.
Figure 6 shows the fundus photograph taken on the 21st day after administration of each composition with different contents of inavogliflozin and administration of ranibizumab in combination.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples only illustrate the present invention, and the present invention is not limited by the following examples.

Preparation Example 1. Preparation of eye drop formulation containing SGLT-2 inhibitor

In a transparent glass vial, excipients excluding the main component and water for injection were sequentially weighed and added. Then, it was heated to about 60-80 °C and stirred to make a transparent solution, and the corresponding amount of the main ingredient was weighed and slowly put into a glass vial to completely dissolve. It was sterilized by sterilization filtration through a 0.2 μm filter made of PVDF and filled in an appropriate sterile container.

Inavogliflozin, one of the SGLT-2 inhibitors, was used as the main component, and the composition for each concentration is as summarized below.

Example 1. Inabogliflozin 0.5% Containing Eye Drops

Example 2. Inabogliflozin 2.0% Containing Eye Drops

Example 3. Inabogliflozin 8.0% Containing Eye Drops

Example 4. Inavogliflozin-containing oral preparation

After dispersing inavogliflozin in 0.5% (w/v) methylcellulose solution, it was orally administered.

Comparative Example 1. Ranibizumab (Ranibizumab)

As a positive control, Lucentis (LUCENTIS ^® ) was purchased and administered.

Experimental Example 1. Confirmation of pharmacological effect on diabetic retinopathy

1-1. Production of diabetic retinopathy animal model

Brown Norway rat, BN/SsN Slc was purchased and used. Male 6-week-old rats were bred with a temperature of 23±3 ℃, relative humidity of 55±15%, ventilation frequency of 10-20 times/hr, illumination time of 12 hours, and illuminance of 150-300 Lux during the breeding period. Environmental conditions such as temperature/humidity, ventilation frequency, and illuminance of the animal room were measured regularly. During the period of acclimatization, administration, and observation, they were bred in a polycarbonate breeding box for rodents (W 170 x L 235 x H 125 mm) at no more than 3 animals/bringing box, and the breeding box, rug, and water bottle were exchanged at least once a week.

Administer streptozotocin (STZ) to animals determined to be healthy during the acclimatization period, and measure blood glucose on the 7th day of administration. The distribution was randomized so that the average blood glucose was distributed as evenly as possible. On the day of induction, streptozotocin was administered as a single intravenous administration at a dose of 60 mg/kg.

1-2. Composition and dosage setting of the test group

The composition and dosage settings of the test group are shown in Table 1 below. G1 is a normal control group in which diabetic retinopathy is not induced, G2 is a group administered with a vehicle as a control group inducing diabetic retinopathy, and G3 is a positive control, Comparative Example 1 (LUCENTIS ^® ) administration group, G4 is Example 2 administration group. The vehicle is a solution of the remaining ingredients except for the active ingredient, inavogliflozin.

In the case of intravitreal administration, 10 μL of Comparative Example 1 was administered to the right eye of the animal under anesthesia using a syringe equipped with a 31 gauge needle, and administered once on the day of administration.

In the case of eye drop administration, after calibrating the animal, 10 μL of each test substance was administered to the center of the right eye cornea using a pipette. From the start date of each administration (Day 0) to the 20th day after the start of administration, it was administered by eye drops once/day.

1-3. Fundusography and retinal fluorescence intensity analysis

On the 21st day after the start of administration of the test substance in each group, a mydriatic drug (midriacil 1% eye drop) was instilled into the right eye of the animal, anesthesia was administered, and 2% fluorescein sodium salt solution was administered. After injection through the caudal vein, images were taken within 2 minutes using a fundus camera (TRC-50IX, TOPCON, Japan). Retinal identification and efficacy were evaluated using retinal fluorescence fundus photographs. For image analysis, fluorescein intensity in non-vascular regions of retina was measured using ImageJ software (NIH, Bethesda, MD), and the average value of the normal control group (G1) was used as a standard (100%). The relative level (%) of each individual measured value was analyzed and compared between groups.

As a result, as shown in Table 2 and FIG. 1, the fluorescence intensity level of all diabetes-inducing groups (G2 to 4) on the 21st day after the start of administration of each test substance was significantly higher than that of the normal control group (G1) (p <0.001 or p<0.05), especially in G2, the fluorescence intensity was high. When administered in Example 2 of the present invention, it was confirmed that a slightly lower level of fluorescence intensity than the positive control group was exhibited. From this, it was confirmed that the increase in retinal vascular permeability due to diabetic retinopathy can be inhibited when the composition of the present invention is administered.

In addition, as shown in FIG. 2 , in the case of G2, a wide range of fluorescence leakage was observed, and it was confirmed that the fluorescence leakage was reduced in G3 and G4.

The composition of Example 2 of the present invention, unlike Comparative Example 1, which is a positive control group, was conveniently administered to the eye as an eye drop, not administered through injection into the vitreous body, and while the therapeutic effect was maintained at the level of the positive control group, the convenience of taking medication was greatly increased. .

1-4. statistical analysis

Normality was assumed for the experimental results, and the test was performed by parametric one-way ANOVA. If the ANOVA result was significant, a post hoc test was performed using Dunnett's multiple comparison test.

Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and when the p-value was less than 0.05, it was determined to be statistically significant.

Experimental Example 2. Pharmacokinetic analysis according to the SGLT-2 inhibitor content

2-1. Laboratory Animals and Breeding Environments

44 male New Zealand White Rabbits were purchased. During the 8-day acclimatization period after acquisition, general symptoms were observed to confirm the health status, and 40 healthy animals were used for the test.

During the test period, the temperature was 23±3 ℃, relative humidity 55±15 %, ventilation frequency of 10-20 times/hr, lighting time of 12 hours, and illuminance of 150-300 Lux were set. Environmental conditions such as , ventilation frequency and illuminance were measured regularly.

The weights of animals determined to be healthy during the acclimatization period were measured and randomly distributed so that the average weight of each group was distributed as evenly as possible according to the ranked weights.

2-2. Composition and dosage setting of the test group

The composition of the test group and the dose setting of the test substance are shown in Table 3 below. G1 to G3 are the eye drops administration group of Examples 1 to 3 according to the content of inavogliflozin, and G4 is the oral administration group of Example 4.

Eye drops were administered to both eyes, and 50 μL/eye was administered at one time. After calibrating the animals, the materials of Examples 1 to 3 were instilled in the center of the corneas of both eyes using a pipette.

Oral administration was administered once by inserting a catheter for oral administration into the stomach on the day of administration, and 2.5 mL/kg was administered at one time of administration.

2-3. blood draw

Blood was collected through the jugular vein, and about 1 mL of whole blood was collected at 1, 4, 8, 16, and 24 hours after administration of each substance of Examples 1 to 4. All processes from blood collection to plasma storage were performed in an ice-cooled state at about 4 °C. The blood sample was placed in a tube to which 10 μL of heparin (Sodium heparin 500 IU/mL) was added, centrifuged at 3.000 rpm at 4 °C for 10 minutes, and only the supernatant, plasma, was separated and dispensed into a micro tube. .

2-4. sample collection

At 1, 4, 8, 16 and 24 hours (5 points) after administration of each substance in Examples 1 to 4, the animals were euthanized and then the eyes were removed and the retinas (including the choroid) and vitreous were collected from both eyes. Each was placed in a microtube. After measuring the weight, the sample was stored in a deep freezer set at about -70 °C or lower until analysis.

2-5. PK analysis results

The concentration of each group in plasma, vitreous, retina and choroid with time was obtained using LC-MS/MS analysis, and non-compartmental analysis using WinNonlin ^® 4.2 (Pharsight Corp., Cary, NC, USA) software. Pharmacokinetic parameters (PK parameters) were calculated.

As a result, as shown in Table 4, the maximum observed plasma concentration (C _max ) in plasma, vitreous body, retina and choroid increased proportionally as the inavogliflozin content increased. In particular, in the case of eye drop administration, even in the case of G1 administered with Example 1 containing inabogliflozin at the lowest content, it was confirmed that it exhibited a higher level in the vitreous, retina and choroid compared to orally administered G4, It was confirmed that the concentration in the vitreous body, retina and choroid was maintained higher when administered by eye drops ( FIGS. 3 and 4 ). This shows that the therapeutic effect of ophthalmic diseases in the eye can be effectively exhibited when the eye drops are administered.

Experimental Example 3. Confirmation of pharmacological effect on diabetic retinopathy according to SGLT-2 inhibitor content

3-1. animal model

Brown Norway rats were used. 42 6-week-old males were obtained. During the 14-day acclimatization period after acquisition, general symptoms were observed to confirm the health condition, and 35 healthy males were used for the test.

During the test period, the temperature was 23±3 ℃, relative humidity 55±15 %, ventilation frequency of 10-20 times/hr, lighting time of 12 hours, and illuminance of 150-300 Lux were set. Environmental conditions such as , ventilation frequency and illuminance were measured regularly.

Administer streptozotocin (STZ) to animals determined to be healthy during the acclimatization period, and measure blood glucose on the 7th day of administration. The distribution was randomized so that the average blood glucose was distributed as evenly as possible. On the day of induction, streptozotocin was administered as a single intravenous administration at a dose of 60 mg/kg.

3-2. Composition and dosage setting of the test group

The composition of the test group and the dosage setting of the test substance are as shown in Table 4 below. G1 is a normal control group, G2 is an induced control group, G3 is the administration group of Comparative Example 1, which is a positive control group, G4 to G6 are the eye drops administration group of Examples 1 to 3, respectively, and G7 is the combination administration group of Example 2 and Comparative Example 1. .

In the case of intravitreal administration, 10 μL of Comparative Example 1 was administered to the right eye of the animal by using a syringe equipped with a 31 gauge needle while the animal was anesthetized, and administered once on the day of administration.

For eye drop administration, after calibrating the animal, 10 μL of each test substance was administered to the center of the right eye cornea using a pipette. From the start date of each administration (Day 0) to the 20th day after the start of administration, it was administered by eye drops once/day.

3-3. Fundusography and retinal fluorescence intensity analysis

On the 21st day after the start of administration of the test substance in each group, a mydriatic drug (midriacil 1% eye drop) was instilled into the right eye of the animal, anesthesia was administered, and 2% fluorescein sodium salt solution was administered. After injection through the caudal vein, images were taken within 2 minutes using a fundus camera (TRC-50IX, TOPCON, Japan). Retinal identification and efficacy were evaluated using retinal fluorescence fundus photographs. For image analysis, fluorescein intensity in non-vascular regions of retina was measured using ImageJ software (NIH, Bethesda, MD), and the average value of the normal control group (G1) was used as a standard (100%). The relative level (%) of each individual measured value was analyzed and compared between groups.

As a result, as shown in Table 6 and Figure 5, the fluorescence intensity level of all diabetes-inducing groups (G2 to G7) on the 21st day after the start of administration of each test substance was significantly higher than that of the normal control group (G1), especially The fluorescence intensity in G2 was high.

In the case of G1 administered with Example 1 containing inabogliflozin in the lowest content, the fluorescence intensity was reduced to a level similar to that of the positive control, G3, and the fluorescence intensity of G5 and G6 with increased content of inabogliflozin was observed. In this case, it was confirmed that the fluorescence intensity was further reduced compared to the positive control, indicating a more excellent therapeutic effect.

In addition, when Example 2 and a positive control, LUCENTIS ^® , were administered together (G7), the fluorescence intensity was reduced to a level similar to that of G6 administered with a high content of inavogliflozin. Even if it does not contain gin in a high content, it was confirmed that by using it in combination with a therapeutic agent that inhibits anti-VEGF, such as Lucentis ^® , it can exhibit the same therapeutic effect as administration of a high content of inavogliflozin.

In addition, as shown in FIG. 6 , in the case of G2, fluorescence leakage was observed in a wide range, but it was confirmed that fluorescence leakage was reduced in all test substance administration groups (G3 to G7).

In particular, as the content of inavogliflozin increased, fluorescence leakage was further reduced, and when Example 2 and a positive control, LucENTIS ^® were administered together (G7), a high content of inavogliflozin was administered It was confirmed that the fluorescence leakage was reduced to a level similar to that of G6. As such, it was confirmed that the therapeutic effect on diabetic retinopathy appears when the composition of the present invention is administered by eye drops through fundus photography, and even if it does not contain a high content of inavogliflozin by combining it with a therapeutic agent that inhibits anti-VEGF It was confirmed that a similar level of therapeutic effect to that administered in a high dose can be exhibited.

The composition of the present invention can effectively treat ocular diseases by maintaining a high drug concentration in the eye, such as the retina and choroid, compared to oral administration by newly discovering the administration route of the SGLT-2 inhibitor, and the conventional treatment for ophthalmic diseases. Unlike administration through injection into the vitreous body, it is conveniently administered to the eye as an eye drop, and has the effect of greatly increasing the convenience of administration.

3-4. statistical analysis

Normality was assumed for the experimental results, and the test was performed by parametric one-way ANOVA. If the ANOVA result was significant, a post hoc test was performed using Dunnett's multiple comparison test.

Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and when the p-value was less than 0.05, it was determined to be statistically significant.

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.

Claims (10)

A pharmaceutical composition for preventing or treating diabetic eye disease, comprising an SGLT-2 (Sodium-glucose cotransporter 2) inhibitor. The method of claim 1,
The SGLT-2 inhibitor is inavogliflozin (Enavogliflozin), a pharmaceutical composition for preventing or treating diabetic eye disease. 3. The method of claim 2,
The inavogliflozin (Enavogliflozin) is a pharmaceutical composition for the prevention or treatment of diabetic eye disease, which consists of the structure of the following formula (1).
[Formula 1]

According to claim 1,
The diabetic eye disease is at least one selected from the group consisting of diabetic retinopathy, macular edema, cataract, glaucoma, and paralytic strabismus, a composition for preventing or treating diabetic eye disease. According to claim 1,
The composition is for eye drop administration, the composition for preventing or treating diabetic eye disease. According to claim 1,
The composition is an anti-VEGF (Vascular endothelial growth factor) antibody or a pharmaceutical composition for preventing or treating diabetic eye disease, further comprising a substance that binds to VEGF and inhibits the action of VEGF. 7. The method of claim 6,
The anti-VEGF antibody is ranibizumab (Ranibizumab), or bevacizumab (Bevacizumab), a pharmaceutical composition for preventing or treating diabetic eye disease. 7. The method of claim 6,
The substance inhibiting the action of VEGF by binding to the VEGF is aflibercept (Aflibercept), a pharmaceutical composition for preventing or treating diabetic eye disease. A method for preventing or treating diabetic eye disease, comprising administering the composition of claim 1 to a subject other than a human. 10. The method of claim 9,
A method for preventing or treating diabetic eye disease, comprising administering together an anti-VEGF antibody or a substance that binds to VEGF and inhibits the action of VEGF.

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