Olopatadine hydrochloride eye drops and use thereof in treating ocular neovascular disease

Abstract

The application provides an olopatadine hydrochloride eye drop and application thereof in treating ocular neovascular disease. Researches of the application show that olopatadine or a salt thereof can inhibit abnormal expression of VEGF and thus reduce neovascular exudation, and can be used in manufacture of ocular biological medicines, chemical medicine raw materials and preparation. Further, the olopatadine hydrochloride is made into an eye drop capable of penetrating into the fundus, and the olopatadine hydrochloride eye drop has the same or better long-term curative effect (about 35% inhibition is maintained for 24 days) than the existing anti-VEGF injection medicine (ranibizumab eye injection) and has smaller side effects. Since the eye drop is a non-invasive treatment, local administration does not need complicated operation, and thus the patient compliance is obviously improved; and the eye drop composition is stable and easy to mass produce.

Description

Technical Field

[0001] This invention relates to the field of ophthalmic drug technology, and more specifically, to an olopatadine hydrochloride eye drop and its application in the treatment of ocular neovascular diseases. Background Technology

[0002] Ocular neovascularization is a group of serious eye diseases caused by abnormal angiogenesis, commonly seen in diabetic retinopathy, wet age-related macular degeneration (AMD), choroidal neovascularization, and other diseases.

[0003] VEGF (vascular endothelial growth factor) is a group of glycoproteins that promote angiogenesis and increase vascular permeability, with VEGF-A being the most prevalent pro-angiogenic subtype. It activates downstream signaling pathways by binding to receptors (VEGFR-1 and VEGFR-2) on the surface of vascular endothelial cells, inducing endothelial cell proliferation, migration, and vascular leakage, thereby promoting angiogenesis. Under conditions of hypoxia, inflammation, or metabolic abnormalities (such as diabetes), VEGF expression in retinal or choroidal tissues is significantly elevated. For example, in diabetic retinopathy, hyperglycemia leads to retinal ischemia and hypoxia, stimulating VEGF-A secretion, triggering abnormal angiogenesis, and potentially leading to retinal detachment or glaucoma.

[0004] VEGF is a core regulator of ocular neovascularization, and anti-VEGF therapy has become the preferred treatment for these diseases. Olopatadine or its salts (e.g., olopatadine hydrochloride) are second-generation antihistamines commonly used to treat allergic rhinitis and urticaria. They exert their anti-allergic effects by antagonizing histamine H1 receptors and inhibiting the release of inflammatory mediators. Their characteristics include rapid onset of action, fewer side effects, and minimal impact on the central nervous system, making them suitable for patients with allergic diseases requiring long-term medication. Currently, there are no reports on the anti-VEGF effects of olopatadine or its salts.

[0005] Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs is currently the first-line treatment for ocular neovascularization diseases. Examples include ranibizumab ophthalmic injection and aflibercept intravitreal injection, which have achieved good results. However, there are certain limitations. Anti-VEGF drugs are mainly delivered to the fundus via intravitreal injection, requiring frequent injections to maintain efficacy. Repeated invasive procedures lead to poor compliance and pose a risk of infection. Therefore, there is a need to develop safe and easy-to-use non-invasive therapies.

[0006] Olopatadine hydrochloride eye drops are a topical ophthalmic medication used to suppress immediate-type hypersensitivity reactions. It is primarily used for allergic conjunctivitis. Common brand names include Patanol, Zipitor, and Zhengxin. Olopatadine hydrochloride eye drops are available in 0.1% (5 mL: 5 mg, calculated as olopatadine) and 0.2% (2.5 mL: 5 mg, calculated as olopatadine) strengths. However, existing olopatadine hydrochloride eye drops are mainly used for ocular surface diseases. Due to their short retention time on the ocular surface, they cannot effectively penetrate the fundus, limiting their application in the treatment of fundus diseases. Summary of the Invention

[0007] The purpose of this invention is to overcome the above-mentioned defects and deficiencies in the prior art and to provide the application of olopatadine or its salt as the sole active ingredient in the preparation of anti-vascular endothelial growth factor (VEGF) drugs.

[0008] A second object of the present invention is to provide the use of olopatadine or its salt as the sole active ingredient in the preparation of a medicament for treating ocular neovascular diseases.

[0009] The third objective of this invention is to provide an olopatadine hydrochloride eye drop.

[0010] A fourth object of the present invention is to provide the use of olopatadine hydrochloride eye drops in the preparation of a medicament for treating ocular neovascular diseases.

[0011] The above-mentioned objective of this invention is achieved through the following technical solution: This invention demonstrates that olopatadine or its salts can inhibit abnormal VEGF expression, thereby reducing neovascularization and exudation. Furthermore, olopatadine hydrochloride was formulated into an eye drop that can penetrate the fundus, showing that olopatadine hydrochloride eye drops have equal or better long-term efficacy than existing anti-VEGF injectable drugs (ranibizumab ophthalmic injection) (maintaining approximately 35% inhibition after 24 days). Since the eye drops are a non-invasive treatment, local administration does not require complex surgery, significantly improving patient compliance.

[0012] Therefore, this invention first provides the application of olopatadine or its salt as the sole active ingredient in the preparation of anti-vascular endothelial growth factor (VEGF) drugs. It can be used in the manufacture of ocular biopharmaceuticals, and as a raw material and formulation for chemical pharmaceuticals.

[0013] The use of olopatadine or its salt as the sole active ingredient in the preparation of drugs for the treatment of ocular neovascularization.

[0014] Furthermore, the drug is an ophthalmic preparation.

[0015] Preferably, the ophthalmic preparation includes, but is not limited to, ophthalmic injections, eye drops, ophthalmic gels, ophthalmic ointments, or any other dosage form pharmaceutically suitable for topical ophthalmic use.

[0016] Furthermore, the olopatadine or its salt is olopatadine hydrochloride.

[0017] The present invention also provides an olopatadine hydrochloride eye drop containing 0.1% to 0.2% (w / v) olopatadine hydrochloride and 0.08% to 0.12% (w / v) sodium hyaluronate.

[0018] In the aforementioned olopatadine hydrochloride eye drops, olopatadine hydrochloride is the sole active ingredient, while sodium hyaluronate can enhance the drug's retention time on the ocular surface, thereby enabling olopatadine hydrochloride to effectively penetrate into the fundus and treat fundus diseases, such as anti-VEGF therapy.

[0019] Furthermore, the eye drops also contain an antibacterial agent, an osmotic pressure regulator, a pH regulator, and water for injection; the osmotic pressure regulator adjusts the osmotic pressure of the eye drops to 280–330 mOsm / L; the pH regulator adjusts the pH of the eye drops to 6.8–7.2 to ensure ophthalmic safety.

[0020] Preferably, the antibacterial agent is 0.003-0.01% benzalkonium chloride.

[0021] Preferably, the osmotic pressure regulator is sodium chloride or boric acid.

[0022] Preferably, the pH adjuster is disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0023] Preferably, the content of olopatadine hydrochloride is 0.15% (w / v), and the content of sodium hyaluronate is 0.1% (w / v).

[0024] The present invention also provides the use of any of the above-described olopatadine hydrochloride eye drops in the preparation of a medicament for treating ocular neovascular diseases.

[0025] Furthermore, the ocular neovascular disease is a fundus neovascular disease.

[0026] Preferably, the fundus neovascular disease is a retinal neovascular disease or a choroidal neovascular disease.

[0027] Preferably, the retinal neovascularization diseases include diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, etc. The choroidal neovascularization diseases include wet age-related macular degeneration (AMD), etc., which can alleviate macular edema and neovascularization by inhibiting abnormal VEGF expression.

[0028] Compared with the prior art, the present invention has the following beneficial effects: This invention demonstrates that olopatadine or its salts can inhibit abnormal VEGF expression, thereby reducing neovascularization and exudation. Furthermore, olopatadine hydrochloride was formulated into an eye drop that can penetrate the fundus, showing that olopatadine hydrochloride eye drops have equal or better long-term efficacy than existing anti-VEGF injectable drugs (ranibizumab ophthalmic injection) (maintaining approximately 35% inhibition after 24 days), with fewer side effects. Since the eye drops are a non-invasive treatment, local administration does not require complex surgery, significantly improving patient compliance. Moreover, the eye drop composition is stable and easy to mass-produce. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments in the specification, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

[0030] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0031] Example 1 Olopatadine hydrochloride (0.15 g) and sodium hyaluronate (1.0 g) were dissolved in sterile water for injection to prepare a 1000 mL solution. The pH of the solution was adjusted to 7.0 with phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate), and the osmotic pressure was adjusted to 330 mOsmol / kg with osmotic pressure regulator (sodium chloride). The solution was then terminally sterilized and dispensed to obtain 0.15% w / v olopatadine hydrochloride eye drops.

[0032] Example 2 Olopatadine hydrochloride (0.1 g) and sodium hyaluronate (1.0 g) were dissolved in sterile water for injection to prepare a 1000 mL solution. The pH of the solution was adjusted to 7.0 with phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate), and the osmotic pressure was adjusted to 330 mOsmol / kg with osmotic pressure regulator (sodium chloride). The solution was then terminally sterilized and dispensed to obtain 0.1% w / v olopatadine hydrochloride eye drops.

[0033] Example 3 Olopatadine hydrochloride (0.2 g) and sodium hyaluronate (1.0 g) were dissolved in sterile water for injection to prepare a 1000 mL solution. The pH of the solution was adjusted to 7.0 with phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate), and the osmotic pressure was adjusted to 330 mOsmol / kg with osmotic pressure regulator (sodium chloride). The solution was then terminally sterilized and dispensed to obtain 0.2% w / v olopatadine hydrochloride eye drops.

[0034] Example 4 Olopatadine hydrochloride (0.15g) and sodium hyaluronate (0.8g) were dissolved in sterile water for injection to prepare a 1000mL solution. The pH of the solution was adjusted to 7.0 with phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate), and the osmotic pressure was adjusted to 330mOsmol / kg with osmotic pressure regulator (sodium chloride). The solution was then terminally sterilized and dispensed to obtain 0.2% w / v olopatadine hydrochloride eye drops.

[0035] Example 5 Olopatadine hydrochloride (0.15g) and sodium hyaluronate (1.2g) were dissolved in sterile water for injection to prepare a 1000mL solution. The pH of the solution was adjusted to 7.0 with phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate), and the osmotic pressure was adjusted to 330mOsmol / kg with osmotic pressure regulator (sodium chloride). The solution was then terminally sterilized and dispensed to obtain 0.2% w / v olopatadine hydrochloride eye drops.

[0036] Test case Evaluating drug efficacy in a laser-induced VEGF expression model in rabbit eyes: 1. Method C57 / B6 mice were selected to establish a choroidal neovascularization (CNV) model induced by a 532nm argon laser. (The laser point should avoid major blood vessels and be located 2.5–3.0 disc diameters away from the optic nerve head.) The successfully modeled mice were divided into 7 groups of n=5 each, and drugs were administered according to the following experimental groupings.

[0037] Experimental Groups: (1) Experimental group 1: Olopatadine hydrochloride was prepared into a 0.15% w / v injection solution using sterile water for injection, and 100 μL / eye was injected into the vitreous cavity, i.e., 0.15 mg / eye.

[0038] (2) Experimental group 2: The eye drops containing 0.15% w / v olopatadine hydrochloride from Example 1 were administered twice daily (1 drop per eye) for 1 month. (3) Experimental group 3: Similar to Example 1, except that sodium hyaluronate was not added, and 0.15% w / v olopatadine hydrochloride eye drops (without sodium hyaluronate) were prepared; 1 drop was instilled into the eye twice a day for 1 month. (4) Blank group: No treatment was given after laser induction, and an equal amount of normal saline was given daily; (5) Negative control group: eye drops containing only 0.1% w / v sodium hyaluronate + buffer system + osmotic pressure system without olopatadine hydrochloride were administered twice daily (1 drop per eye) for 1 month. (6) Positive control group: Ranibizumab ophthalmic injection was used at a dose of 0.5 mg / eye.

[0039] (7) No medication group: No treatment after laser induction, serving as a natural disease course control.

[0040] Indicator detection: VEGF levels in retinal tissue were measured by ELISA at days 1, 7, and 24, and the rate of decrease was calculated. Choroidal vessels were assessed using fluorescence angiography (FFA) and optical coherence tomography (OCT). The FFA and OCT results were quantified and then compared using a t-test.

[0041] 2. Results (1) The VEGF inhibition effect is shown in Table 1. VEGF expression was slightly increased in the untreated group, while VEGF was downregulated in all treated groups. The injection group (experimental group 1, positive control group) showed the fastest onset of action, and although its early effect was better than that of olopatadine hydrochloride eye drops (experimental group 2), the eye drops had better long-term efficacy. The effect of the injection group after 24 days was slightly lower than that of the eye drops group (experimental group 2). Experimental groups 1 and 2 showed a rapid response within one day, with inhibition exceeding that of the untreated group by more than 33%, significantly better than the sodium hyaluronate carrier alone. Since the olopatadine hydrochloride eye drops in experimental group 3 did not contain sodium hyaluronate, its VEGF inhibition effect was significantly lower than that in experimental group 2; while the eye drops containing only sodium hyaluronate (negative control group) showed no significant effect in VEGF inhibition. This indicates that sodium hyaluronate can enhance the retention time of olopatadine hydrochloride on the ocular surface, thereby allowing olopatadine hydrochloride to effectively penetrate the fundus and effectively treat fundus diseases.

[0042] Table 1 Comparison of VEGF inhibition effects (% decrease ± SE)

[0043] *: The values ​​in the blank group represent the inhibition rate compared to baseline; VEGF expression was slightly increased in the untreated group.

[0044] Key findings: Compared with the control group, the drug group showed an increase of approximately 31%–33% in VEGF inhibition at each time point, and the effect was statistically significant at 7 and 24 days (p<0.05).

[0045] (2) The condition of the choroidal vessels is shown in Table 2, which shows: 1) Time dependence: All treatment groups (experimental groups 1, 2, and 3) showed early onset (1 day), the best effect was achieved at 7 days, and the effect was maintained or slightly decreased at 24 days; 2) Differences in administration routes: The injection group (experimental group 1 and positive control) had a fast onset but significant attenuation; the eye drop group had a stable and long-lasting effect; 3) Dose-response relationship: The effect of experimental group 2 (0.15%) at 24 days was better than that of the injection in experimental group 1, suggesting that it may have better long-term efficacy; Table 2 CNV penetration area (mm) 2 (x±s)

[0046] Note: The initial CNV area baseline value is 4.90±0.40 mm. 2 .

[0047] Based on the results in Tables 1 and 2 above, it is evident that both experimental groups 1 and 2 effectively inhibited VEGF expression and reduced CNV infiltration area, and the VEGF inhibition effect was consistent with that of choroidal vessels. This indicates that olopatadine or its salts can inhibit abnormal VEGF expression and thus reduce neovascularization. Further development of olopatadine hydrochloride into an eye drop solution (containing sodium hyaluronate) that can penetrate the fundus showed that olopatadine hydrochloride eye drops have the same or better long-term efficacy as existing anti-VEGF injectable drugs (ranibizumab ophthalmic injection) (maintaining approximately 35% inhibition even after 24 days). Since the eye drops are a non-invasive treatment, local administration does not require complex surgery, significantly improving patient compliance and thus showing greater application potential.

Claims

1. The application of olopatadine or its salt as the sole active ingredient in the preparation of anti-vascular endothelial growth factor drugs.

2. The use of olopatadine or its salt as the sole active ingredient in the preparation of drugs for treating ocular neovascular diseases.

3. The application according to claim 1 or 2, characterized in that, The olopatadine or its salt is olopatadine hydrochloride.

4. An olopatadine hydrochloride eye drop, characterized in that, It contains 0.1%–0.2% (w / v) olopatadine hydrochloride and 0.08–0.12% (w / v) sodium hyaluronate.

5. The olopatadine hydrochloride eye drops according to claim 4, characterized in that, It also contains antibacterial agents, osmotic pressure regulators, pH regulators, and water for injection; the osmotic pressure regulator adjusts the osmotic pressure of the eye drops to 280–330 mOsm / L; the pH regulator adjusts the pH of the eye drops to 6.8–7.

2.

6. The olopatadine hydrochloride eye drops according to claim 5, characterized in that, The antibacterial agent is 0.003-0.01% benzalkonium chloride.

7. The olopatadine hydrochloride eye drops according to claim 5, characterized in that, The pH adjuster is disodium hydrogen phosphate and sodium dihydrogen phosphate.

8. The olopatadine hydrochloride eye drops according to claim 4, characterized in that, The content of olopatadine hydrochloride is 0.15% (w / v), and the content of sodium hyaluronate is 0.1% (w / v).

9. The use of the olopatadine hydrochloride eye drops according to any one of claims 4 to 8 in the preparation of a medicament for treating ocular neovascular diseases.

10. The application according to claim 2 or 9, characterized in that, The ocular neovascular disease is either retinal neovascular disease or choroidal neovascular disease.

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