Application of rucotinib in treatment of age-related macular degeneration

Abstract

By constructing an age-related macular degeneration animal model, experimental results in multiple aspects of clinical examination (FFA and ERG), pathological detection (RPE-choroidal patch IB4 fluorescent staining) and the like prove that the rucotinib can be used for effectively treating age-related macular degeneration, especially wet age-related macular degeneration.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to application of ruxolitinib in treating age-related macular degeneration. Background Art

[0002] Age-related macular degeneration, also known as age-related macular degeneration (AMD), is an aging change in the structure of the macula. This disease mostly occurs in people over 45 years old, and its prevalence increases with age. It is currently an important cause of blindness in middle-aged and elderly people. Age-related macular degeneration (AMD) is a type of disease that mainly affects the cones and rods in the macula, retinal pigment epithelial cells (RPE), Bruch's membrane and choroid. Progressive AMD includes two forms: dry AMD (geographic atrophy) and wet AMD (neovascular AMD). Dry age-related macular degeneration is mainly characterized by the formation of small, slightly yellow deposits (drusen) on the fundus; while the main pathogenic mechanism of wet age-related macular degeneration is that new blood vessels (CNV) grow from the choroid through damaged tissue into the retina, causing bleeding and forming scar tissue.

[0003] AMD is a disease that seriously affects vision and can even cause blindness. So far, modern medicine has not found an exact and effective drug therapy that can prevent the progression of the disease. Even for neovascular AMD, after regular first-line treatment (anti-VEGF treatment), more than 60% of patients still have difficulty achieving significant vision improvement, and many patients even experience decreased vision. Long-term maintenance of anti-VEGF treatment also cannot prevent recurrence of the disease. Therefore, there is still a great need to find a safe and effective method to treat AMD. Summary of the invention

[0004] In order to improve the above technical problems, the present invention provides the use of ruxolitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing age-related macular degeneration (AMD).

[0005] According to an embodiment of the present invention, age-related macular degeneration includes dry age-related macular degeneration and wet age-related macular degeneration (wAMD, also known as neovascular AMD).

[0006] According to an embodiment of the present invention, the types of neovascularization in wet age-related macular degeneration are divided into type I macular neovascularization, type II macular neovascularization, and type III macular neovascularization.

[0007] According to an embodiment of the present invention, age-related macular degeneration also includes subtypes of other special types of neovascular AMD, such as polypoidal choroidal vasculopathy and retino-choroidal anastomosis.

[0008] The present invention also provides the use of ruxolitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing ocular neovascular diseases.

[0009] According to an embodiment of the present invention, the ocular neovascular diseases include wet age-related macular degeneration (neovascular AMD), diabetic retinopathy, and retinopathy of prematurity.

[0010] According to an embodiment of the present invention, the administration dose of the medicament is 1 μg to 100 μg, preferably 5 μg to 50 μg, and for example, it can be 2 μg, 5 μg, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg or any value between any two numerical values.

[0011] According to an embodiment of the present invention, the dosage form of the medicament includes injections, eye drops (such as eye drops).

[0012] According to an embodiment of the present invention, the administration methods of the medicament include intraocular injection administration and mucosal administration (such as eye drop administration);

[0013] Preferably, the injection administration includes intravitreal injection administration, subconjunctival injection administration, and retrobulbar injection administration.

[0014] According to an embodiment of the present invention, the frequency of mucosal administration of the medicament can be once a day, twice a day, three times a day, once every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, once every three weeks, once every four weeks, etc.

[0015] According to an embodiment of the present invention, the frequency of intravitreal injection administration, subconjunctival injection administration, and retrobulbar injection administration of the medicament can be once a week, once every two weeks, once every three weeks, once a month, once every 1.5 months, once every two months, once every 2.5 months, once every three months, etc.; preferably, the administration cycle of the injection administration of the medicament is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc.

[0016] The present invention also provides a method for treating and / or preventing age-related macular degeneration (senile macular degeneration, AMD), the method comprising administering a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof to a patient.

[0017] The present invention also provides a method for treating and / or preventing ocular neovascular diseases, the method comprising administering a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof to a patient.

[0018] Beneficial effects

[0019] The present invention constructs an animal model of age-related macular degeneration, and experimental results from multiple aspects such as clinical examinations (FFA, ERG) and pathological detections (RPE-choroid flat mount IB4 fluorescence staining) confirm that ruxolitinib can effectively treat age-related macular degeneration, especially wet age-related macular degeneration. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It shows the vascular leakage situation after intravitreal injection of ruxolitinib.

[0021] Figure 2 It shows the IB4 fluorescence staining situation after intravitreal injection of ruxolitinib.

[0022] Figure 3 It shows the electroretinogram after intravitreal injection of ruxolitinib.

[0023] Figure 4 It shows the IB4 fluorescence staining situation after intravitreal injection of placebo, ruxolitinib, baricitinib, and tofacitinib. DETAILED DESCRIPTION OF THE INVENTION

[0024] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0025] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0026] Example 1 Construction of a CNV rat model (wAMD model) and evaluation of the therapeutic effect of ruxolitinib on wAMD

[0027] Use a fundus laser to irradiate the fundus of 8-week-old female Brown-Norway (BN) rats. The laser parameters are set as a wavelength of 532 nm, an energy of 300 mW, a duration of 0.05 s, and a laser spot size of 50 μm.

[0028] Group the model rats, with 5 rats in each group, namely the placebo group (control group, the solvent is 10% PEG400), the ruxolitinib group, the baricitinib group, and the tofacitinib group.

[0029] ① On the 2nd, 5th, and 10th days after modeling, use a 33G sterile needle and a Hamilton microsyringe to intravitreally inject 5 μl of placebo, ruxolitinib (10 ng / μl), baricitinib (10 ng / μl), and tofacitinib (20 ng / μl) into the eyes of the rats respectively.

[0030] ② On the 7th and 14th days, after fully dilating the pupils and anesthetizing the BN rats, examinations were conducted using a Optos ultra-widefield scanning laser ophthalmoscope, optical coherence tomography (OCT), fundus fluorescence angiography (FFA), and electroretinogram (ERG).

[0031] ③ After the examinations on the 14th day, the rats were sacrificed, the eyeballs were removed to prepare RPE / choroid spreads, and IB4 fluorescence staining was performed for evaluation to observe the therapeutic effect of the compound.

[0032] Figure 1 Shows the vascular leakage after intravitreal injection of ruxolitinib. From Figure 1 It can be seen that in the CNV animal model after treatment with ruxolitinib, on the 7th day and 14th day of modeling, the vascular leakage was significantly reduced compared with the control group. This indicates that intravitreal injection of ruxolitinib can reduce the neovascular leakage in wAMD.

[0033] Figure 2 Shows the IB4 fluorescence staining after intravitreal injection of ruxolitinib. The staining area of the control group was 10.69 ± 7.020 (%), and the staining area of the ruxolitinib group was 5.336 ± 3.903 (%). From Figure 2 It can be seen that in the CNV animal model after treatment with ruxolitinib, after sacrificing on the 14th day of modeling, IB4 staining was performed using RPE-choroid spreads, and the positively stained area (indicating neovascularization) was significantly reduced, and there was a statistical difference. This indicates that intravitreal injection of ruxolitinib can reduce the progression of CNV.

[0034] Figure 3 Shows the electroretinogram after intravitreal injection of ruxolitinib. From Figure 3 It can be seen that in the CNV animal model after treatment with ruxolitinib, on the 7th day of modeling, the electroretinogram ERG indicated that almost all waves of the retinal ERG (dark-adapted a-wave, dark-adapted b-wave, light-adapted a-wave, etc.) were significantly enhanced compared with the control group, indicating that ruxolitinib can accelerate the functional recovery of the neural retina.

[0035] Figure 4 Shows the IB4 fluorescence staining after intravitreal injection of placebo, ruxolitinib, baricitinib, and tofacitinib. The staining area of the placebo group was 13.93 ± 8.904 (%), the staining area of the ruxolitinib group was 8.986 ± 1.877 (%), the staining area of the baricitinib group was 12.92 ± 6.446 (%), and the staining area of the tofacitinib group was 11.19 ± 5.717 (%). From Figure 4It can be seen that after the CNV animals were treated with ruxolitinib and sacrificed on the 14th day after modeling, IB4 staining was performed using RPE-choroid flat mounts, and the positively stained area (i.e., indicating neovascularization) was significantly reduced. However, after treatment with baricitinib and tofacitinib, there was no obvious effect of reducing neovascularization.

[0036] As described above, the embodiments of the present invention have been described. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of ruxolitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing age-related macular degeneration (AMD).

2. The application according to claim 1, wherein Age-related macular degeneration includes dry age-related macular degeneration and wet age-related macular degeneration; Preferably, the neovascular types of wet age-related macular degeneration include type I macular neovascularization, type II macular neovascularization, and type III macular neovascularization; Preferably, age-related macular degeneration also includes subtypes of other special types of neovascular AMD, such as polypoidal choroidal vasculopathy and retinochoroidal anastomosis.

3. Use of ruxolitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing ocular neovascular diseases.

4. The application according to claim 3, wherein Ocular neovascular diseases include wet age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity.

5. The application according to any one of claims 1-4, characterized in that The administration dose of the medicament is 1 μg to 100 μg, preferably 5 μg to 50 μg.

6. The application according to any one of claims 1-5, characterized in that, The dosage forms of the medicament include injections and eye drops.

7. The application according to any one of claims 1 to 6, characterized in that, The administration methods of the medicament include ocular injection and mucosal administration; Preferably, injection administration includes intravitreal injection, subconjunctival injection, and retrobulbar injection.

8. The application according to claim 7, characterized in that, The frequency of mucosal administration of the medicament can be once a day, twice a day, three times a day, once every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, once every three weeks, once every four weeks; Preferably, the frequency of intravitreal injection, subconjunctival injection, and retrobulbar injection of the medicament can be once a week, once every two weeks, once every three weeks, once a month, once every 1.5 months, once every two months, once every 2.5 months, once every three months, etc.; preferably, the administration cycle of injection administration of the medicament is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc.

9. A method for treating and / or preventing age-related macular degeneration, the method comprising administering a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof to a patient.

10. A method for treating and / or preventing ocular neovascular diseases, the method comprising administering a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof to a patient.

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