Contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization and preparation method thereof

Abstract

The present invention discloses a contact lens care solution for inhibiting corneal hypoxia and corneal neovascularization. The solution contains the following ingredients: withaferin A, disodium edetate, a solubilizing agent, a thickener, an antibacterial agent, an isotonicity regulator, and an appropriate amount of a pH regulator, with the remainder being water for injection. The solution specifically comprises the following steps: first, weighing withaferin A and a solubilizing agent, mixing them, and stirring them thoroughly for later use; second, weighing the above-mentioned weight-to-volume ratio of disodium edetate, a thickener, a pH regulator, an isotonicity regulator, and an antibacterial agent, heating and stirring the mixture in a 60°C water bath until clear and translucent, and then cooling to room temperature; third, adding the mixture from the first step to the solution from the second step, and adjusting the volume with water for injection to obtain a contact lens care solution; and fourth, filtering the obtained care solution through a 0.22 μm microporous membrane for sterilization and aseptically packaging. The solution has good solubility, improves corneal tissue hypoxia and corneal neovascularization caused by contact lens wear, and provides preventive and health benefits.

Description

Technical Field

[0001] The present invention relates to a contact lens care solution, and in particular to a contact lens care solution capable of inhibiting corneal hypoxia damage and corneal neovascularization, and a preparation method thereof. Background Art

[0002] Wearing contact lenses, especially for extended periods, can easily cause corneal hypoxia and lead to corneal neovascularization. The cornea is the transparent front part of the eye and is normally blood-free. It primarily obtains oxygen through the exchange of air and tears. Contact lenses, especially those with low oxygen permeability (such as cosmetic lenses), cover the cornea, reducing its contact with air, thereby reducing its oxygen permeability and causing corneal hypoxia and damage. When the cornea is chronically hypoxic, vascular endothelial growth factor (VEGF) stimulates the growth of blood vessels at the edge of the cornea toward the center, forming new blood vessels. Long-term contact lens wear can also cause chronic inflammation or micro-injury to the cornea, further promoting the formation of new blood vessels. Corneal neovascularization not only affects corneal transparency and leads to decreased vision, but can also cause other serious eye problems, such as corneal ulcers, corneal epithelial detachment, and even blindness. Therefore, corneal hypoxia and corneal neovascularization are the greatest risks for contact lens wearers.

[0003] Our team's previous research has confirmed that withaferin A, a compound extracted from ashwagandha, has dual effects of resisting hypoxic damage and anti-VEGF, and may become a potential ophthalmic drug (Patent No.: 201910398536.6, disclosing a "Application of Withaferin A in the Preparation of a Drug for Treating Ischemic Fundus Diseases"). However, this invention involves systemic administration of withaferin A to treat fundus lesions using a subperitoneal implanted pump. There are also related basic studies internationally that suggest that withaferin A may also be able to treat pathological corneal angiogenesis, but all of these use systemic administration (such as subperitoneal injection). Mohan R, Bargagna-Mohan P et al. Academic Press, 2016, Investigative Ophthalmology & Visual Science, 2012, PLoS One, 2015, Investigative Ophthalmology & Visual Science, 2005 Chemistry & Biology, 2007, 14(6): 623-634. At present, all relevant studies are basic research, and withaferin A is simply dissolved and used systemically, and no attempt has been made to make it into a related pharmaceutical preparation. Our research group has confirmed that withaferin A is an anti-VEGF and angiogenesis-inhibiting compound. If it is used systemically, it will inhibit the formation of cardiovascular collateral circulation and easily induce cardiovascular and cerebrovascular accidents. Therefore, making it into a pharmaceutical preparation for systemic use obviously has more disadvantages than advantages. Therefore, our team turned to studying making it into an ophthalmic preparation for local use to avoid its cardiovascular and cerebrovascular side effects. When people wear contact lenses, contact lens care solution will directly act on the cornea, playing a role similar to eye drops, and is more convenient to use. Therefore, our team formulated with withaferin A and corresponding excipients into a contact lens solution to prevent the greatest risks for contact lens wearers—corneal hypoxia and neovascularization. Currently, no contact lens solution has been shown to inhibit corneal hypoxia and neovascularization, and no research has been reported on a withaferin A contact lens solution. Summary of the Invention

[0004] To achieve the above object, the technical solution adopted by the present invention is:

[0005] A contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization contains the following ingredients, measured by weight to volume: 0.01-0.5 mg / L withaferin A, 0.1-10 g / L disodium edetate, 1-25 g / L dissolution promoter, 2-40 g / L thickener, 0.04-0.2 g / L antibacterial agent, appropriate amounts of isotonicity regulator and pH regulator, and the balance being water for injection.

[0006] A further preferred embodiment is that the dissolution agent is one of Tween 80, propylene glycol, poloxamer, polyethylene glycol, and β-cyclodextrin, or a mixture of any of them.

[0007] A further preferred embodiment is that the thickener is one or a mixture of any of methyl cellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, povidone, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, and carboxymethyl cellulose.

[0008] A further preferred embodiment is that the pH regulator is one of boric acid, borate buffer, phosphate buffer, citrate buffer or a mixture of any of them, and the amount of the pH regulator is based on adjusting the pH value of the care solution to 6.0-8.5.

[0009] A further preferred embodiment is that the osmotic pressure regulator is one of sodium chloride, potassium chloride, boric acid, glucose, and glycerol, or a mixture of any of them; and the amount of the osmotic pressure regulator is used to adjust the osmotic pressure molar concentration ratio to 0.9 to 1.1.

[0010] The method for preparing the contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization comprises the following steps:

[0011] The first step is to weigh withaferin A and a solubilizing agent in the above-mentioned weight-to-volume ratio, mix them, and stir them thoroughly for later use;

[0012] Step 2: Weigh the above-mentioned weight-to-volume ratio of disodium edetate, thickener, pH adjuster, isotonicity adjuster, and antibacterial agent, heat and stir in a 60° C. water bath until clear and translucent, and cool to room temperature;

[0013] The third step is to add the mixed solution of the first step to the solution of the second step, and dilute to volume with water for injection to prepare a contact lens care solution;

[0014] The fourth step is to filter the prepared care solution through a 0.22 μm microporous filter membrane for sterilization and aseptically package it.

[0015] The care solution of the present invention has the following advantages:

[0016] (1) The contact lens care solution with withaferin A added reported in the present invention makes withaferin A have better solubility, fully exerts the anti-inflammatory, anti-oxidative stress and anti-VEGF effects of withaferin A itself, and compared with ordinary contact lens care, it not only has the moisturizing and cleaning effects of ordinary care solutions, but also directly acts on the cornea when wearing contact lenses, improving corneal tissue hypoxia and corneal neovascularization caused by wearing contact lenses, playing a preventive health care function, with clear effects, easy use, and certain conversion value.

[0017] (2) The withaferin A contact lens care solution reported in the present invention is a transparent and clear liquid with good biocompatibility, moderate viscosity, and no irritation to the eyes.

[0018] (3) The withaferin A in the contact lens care solution disclosed in the present invention has good solubility and permeability, and a traditional antibacterial agent (such as polyhexamethylene biguanide) can be added at the same time to enhance the antibacterial function of the care solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Withaferin A contact lens solution improved corneal angiogenesis in mice caused by alkali burns, while traditional contact lens solution had no obvious effect.

[0020] Figure 2 Withaferin A contact lens solution improved corneal angiogenesis in mice induced by suture method, while traditional contact lens solution had no obvious effect. DETAILED DESCRIPTION

[0021] The following examples and experimental examples are merely provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0022] Example 1 DETAILED DESCRIPTION

[0024] The following examples and experimental examples are merely provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0025] Example 1

[0026] The present embodiment describes a contact lens care solution for inhibiting corneal hypoxic damage and corneal neovascularization. The withaferin A contact lens care solution contains the following ingredients, measured by weight to volume: 0.01 mg / L withaferin A, 0.5 g / L disodium edetate, 1 g / L Tween 80, 5.6 g / L povidone K30, 0.1 g / L benzalkonium chloride, 6.2 g / L sodium chloride, 4 g / L sodium dihydrogen phosphate, 7.1 g / L disodium hydrogen phosphate, and the balance being water for injection.

[0027] The dosage of the sodium dihydrogen phosphate and disodium hydrogen phosphate is based on adjusting the pH value of the contact lens care solution to 6.8.

[0028] The amount of sodium chloride used is to adjust the osmotic pressure molar concentration ratio to 0.9.

[0029] The method for preparing a contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization comprises the following steps:

[0030] The first step is to weigh withaferin A and Tween 80 in the corresponding weight-to-volume ratio, mix them and stir them thoroughly for later use;

[0031] Step 2: Weigh the corresponding weight-to-volume ratios of edetate disodium, povidone K30, benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate, and sodium hydrogen phosphate, heat and stir in a 60°C water bath until clear and translucent, and cool to room temperature;

[0032] The third step is to add the mixed solution of the first step to the solution of the second step and make up to volume with water for injection;

[0033] The fourth step is to filter and sterilize the prepared care solution through a 0.22 μm microporous filter membrane and aseptically package it.

[0034] The contact lens care solution is used for treating corneal hypoxia damage and corneal neovascularization caused by wearing contact lenses.

[0035] Example 2

[0036] The present embodiment describes a contact lens care solution for inhibiting corneal hypoxic damage and corneal neovascularization. The withaferin A contact lens care solution contains the following ingredients, measured by weight to volume: 0.1 mg / L withaferin A, 1 g / L disodium edetate, 5 g / L Tween 80, 5.6 g / L povidone K30, 0.1 g / L benzalkonium chloride, 6.2 g / L sodium chloride, 4 g / L sodium dihydrogen phosphate, 7.1 g / L disodium hydrogen phosphate, and the balance being water for injection.

[0037] The dosage of the sodium dihydrogen phosphate and disodium hydrogen phosphate is based on adjusting the pH value of the contact lens care solution to 6.8.

[0038] The amount of sodium chloride used is to adjust the osmotic pressure molar concentration ratio to 0.9.

[0039] The method for preparing a contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization comprises the following steps: first, weighing withaferin A and Tween 80 in corresponding weight-to-volume ratios, mixing them, stirring them thoroughly, and setting aside;

[0040] Step 2: Weigh the corresponding weight-to-volume ratios of edetate disodium, povidone K30, benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate, and sodium hydrogen phosphate, heat and stir in a 60°C water bath until clear and translucent, and cool to room temperature;

[0041] The third step is to add the mixed solution of the first step to the solution of the second step and make up to volume with water for injection;

[0042] The fourth step is to filter and sterilize the prepared care solution through a 0.22 μm microporous filter membrane and aseptically package it.

[0043] The contact lens care solution is used for treating corneal hypoxia damage and corneal neovascularization caused by wearing contact lenses.

[0044] Example 3

[0045] The present embodiment describes a contact lens care solution for inhibiting corneal hypoxic damage and corneal neovascularization. The withaferin A contact lens care solution contains the following ingredients, measured by weight and volume: 0.5 mg / L withaferin A, 5 g / L disodium edetate, 10 g / L Tween 80, 5.6 g / L povidone K30, 0.1 g / L benzalkonium chloride, 6.2 g / L sodium chloride, 4 g / L sodium dihydrogen phosphate, 7.1 g / L disodium hydrogen phosphate, and the balance being water for injection.

[0046] The dosage of the sodium dihydrogen phosphate and disodium hydrogen phosphate is based on adjusting the pH value of the contact lens care solution to 6.8.

[0047] The amount of sodium chloride used is to adjust the osmotic pressure molar concentration ratio to 0.9.

[0048] The method for preparing a contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization comprises the following steps: first, weighing withaferin A and Tween 80 in corresponding weight-to-volume ratios, mixing them, stirring them thoroughly, and setting aside;

[0049] Step 2: Weigh the corresponding weight-to-volume ratios of edetate disodium, povidone K30, benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate, and sodium hydrogen phosphate, heat and stir in a 60°C water bath until clear and translucent, and cool to room temperature;

[0050] The third step is to add the mixed solution of the first step to the solution of the second step and make up to volume with water for injection;

[0051] The fourth step is to filter and sterilize the prepared care solution through a 0.22 μm microporous filter membrane and aseptically package it.

[0052] The contact lens care solution is used for treating corneal hypoxia damage and corneal neovascularization caused by wearing contact lenses.

[0053] The dissolution promoter may also be one of propylene glycol, poloxamer, polyethylene glycol, and β-cyclodextrin, or a mixture of any of Tween 80, propylene glycol, poloxamer, polyethylene glycol, and β-cyclodextrin.

[0054] The thickener can also be one of polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, povidone, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, and carboxymethyl cellulose, or a mixture of any of methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, povidone, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, and carboxymethyl cellulose.

[0055] The pH regulator can also be one of borate buffer, phosphate buffer, citrate buffer or a mixture of boric acid, borate buffer, phosphate buffer and citrate buffer. The amount of the pH regulator is based on adjusting the pH value of the care solution to 6.0-8.5.

[0056] The osmotic pressure regulator can also be one of potassium chloride, boric acid, glucose, and glycerol, or a mixture of any of sodium chloride, potassium chloride, boric acid, glucose, and glycerol; and the amount of the osmotic pressure regulator is used to adjust the osmotic pressure molar concentration ratio to 0.9 to 1.1.

[0057] The antibacterial agent can also be one of benzalkonium chloride, benzalkonium bromide and polyquaternium-1, or a mixture of any of ethylhydroxybenzoate, benzalkonium chloride, benzalkonium bromide and polyquaternium-1.

[0058] In order to further demonstrate the effects of the present invention, the in vivo experimental results of two animal models are provided as follows:

[0059] In order to further demonstrate the effects of the present invention, the in vivo experimental results of two animal models are provided as follows:

[0060] like Figure 1 As shown in the results, withaferin A contact lens solution improved corneal angiogenesis in mice induced by alkali burn, while traditional contact lens solution had no significant effect.

[0061] This study used a classic mouse corneal alkali burn model to induce corneal neovascularization. Healthy, wild-type female C57 mice, 6-8 weeks of age, were selected. All mice had shiny, non-ablative hair, normal ocular examination, clear refractive media, and normal fundi. They were randomly divided into: 1. control group; 2. alkali burn group; 3. alkali burn combined with conventional contact lens solution; and 4. alkali burn combined with WFA (withaferin A) contact lens solution, with 20 mice in each group. Groups 3 and 4 received the solution once daily, mimicking the frequency of daily contact lens solution use. After 14 days of treatment, corneal neovascularization was scored microscopically according to the following criteria: 0 = no neovascularization, no neovascularization at the limbus; 1 = mild neovascularization, neovascularization originating from the limbus; 2 = moderate neovascularization, neovascularization originating from the limbus and extending toward the center of the cornea; and 3 = severe neovascularization, neovascularization originating from the limbus and reaching and / or crossing the center of the cornea. Figure 1 The results showed that withaferin A contact lens solution significantly improved corneal angiogenesis in mice, while the traditional contact lens solution group did not significantly improve corneal angiogenesis in mice. Figure 1 NS = no difference, **p < 0.01.

[0062] like Figure 2As shown, withaferin A contact lens solution improved corneal angiogenesis in mice induced by suture method, while traditional contact lens solution had no significant effect.

[0063] This experiment chose the classic suture method to induce corneal angiogenesis. Healthy wild-type female ICR mice, aged 6-8 weeks. All mice had shiny hair, no hair loss, no abnormalities in eye examination, clear refractive media, and normal fundus. They were randomly divided into: 1. control group; 2. suture group; 3. suture + traditional contact lens care solution group; 4. suture + WFA contact lens care solution group, with 20 mice in each group. Among them, groups 3 and 4 were given care solution once a day to simulate the daily use frequency of contact lens care solution. After 14 days of intervention, if Figure 2 Under a microscope, the angiogenesis of each group was compared by counting the angiogenesis area. The results showed that the Withaferin A care solution significantly improved the angiogenesis of the mouse cornea, while the Withaferin A solution did not significantly improve the angiogenesis of the mouse cornea. Figure 2 NS = no difference, ***p < 0.001.

[0064] The in vivo experimental results of the above two animal models show that the use of traditional contact lens care solutions has no improvement effect on corneal angiogenesis. The withaferin A contact lens care solution added withaferin A and the corresponding solvent described in this patent acts directly on the cornea when wearing contact lenses. It not only has the moisturizing and cleansing effects of conventional care solutions, but also prevents the biggest hidden dangers of people wearing contact lenses - corneal hypoxia damage and neovascularization. It has clear effects, is easy to use, and has clear application value and market value.

Claims

1. A contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization, characterized in that: The composition is as follows: withaferin A 0.01-0.5 mg / L, edetate disodium 0.1-10 g / L, dissolution enhancer 1-25 g / L, thickener 2-40 g / L, antibacterial agent 0.04-0.2 g / L, appropriate amounts of isotonicity regulator and pH regulator, and the balance is water for injection. The dissolution promoter is one of Tween 80, propylene glycol, poloxamer, polyethylene glycol, and beta-cyclodextrin, or a mixture of any of them.

2. The contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization according to claim 1, characterized in that: The thickener is one or a mixture of any of methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, povidone, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, and carboxymethylcellulose.

3. The contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization according to claim 1, characterized in that: The pH regulator is one of boric acid, borate buffer, phosphate buffer, and citrate buffer, or a mixture of any of the above. The amount of the pH regulator is based on adjusting the pH value of the care solution to 6.0 to 8.

5.

4. The contact lens care solution for inhibiting corneal hypoxia damage and corneal neovascularization according to claim 1, characterized in that: The isotonicity regulator is one of sodium chloride, potassium chloride, boric acid, glucose, and glycerol, or a mixture of any of them; and the dosage of the isotonicity regulator is to adjust the osmotic pressure molar concentration ratio to 0.9-1.1.

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