A soaking solution for a contact lens, a method of preparation, and a contact lens

Abstract

The application provides an immersion solution for a corneal contact lens, a preparation method and the corneal contact lens, and the immersion solution is prepared from the following raw materials in mass percentage: letastigmine 0.01-0.15%; buffer salt 0.1-2%; sodium chloride 0.2-1.2%; sodium thiosulfate 0-0.5%; and pure water 97-99%. The immersion solution for the corneal contact lens prepared by the application can well interact with water molecules in the corneal contact lens, so that the drug molecules in the immersion solution are well replaced in the corneal contact lens, the drug molecules are retained in the gel network of the corneal contact lens, high drug loading is achieved, the bioavailability of the drug is improved, the corneal contact lens prepared by the immersion solution has a drug slow-release effect, directly acts on the eyes and can reduce the toxic and side effects of the drug.

Description

Technical Field

[0001] This invention relates to the field of corneal contact lens technology, and more specifically, to an immersion solution for corneal contact lenses, a preparation method thereof, and a corneal contact lens. Background Technology

[0002] Eye health affects people of all ages and throughout their entire lifespan. Dry eye is the most common ocular surface disease worldwide. Influenced by lifestyle changes and the widespread use of electronic products, the incidence of dry eye is constantly rising, with a global incidence rate of approximately 5.5%-33.7%; in my country, the incidence rate is about 21%-30%, and it is showing a trend of affecting younger people, becoming a significant issue affecting the eye health of the nation.

[0003] The rate of seeking medical attention for dry eye in China is low, and available treatment options are limited. Currently, the most common treatments are artificial tears and immunosuppressants, but most patients do not achieve satisfactory results. Globally, the most commonly used anti-inflammatory drug for dry eye treatment is cyclosporine A ophthalmic emulsion Restasis. ® Lifitegrast eye drops (Xiidra) ® And Xiidra ® Compared to Restasis ® It works faster, with symptom improvement observed after two weeks of treatment in two phase III clinical trials, while Restasis... ® It typically takes 6 weeks of treatment to take effect, but 5%-25% of patients receive Xiidra. ® Side effects such as irritation at the application site, taste disturbance, and decreased vision may occur later.

[0004] Lifitegrast is a novel small-molecule integrin inhibitor and lymphocyte function-associated antigen 1 (LFA-1) antagonist that blocks the interaction between LFA-1 and its homologous ligand, intercellular adhesion molecule-1 (ICAM-1), thus interfering with the overexpression of ICAM-1 in the cornea and conjunctiva, which causes dry eye syndrome. The commercially available lifitegrast formulation is Xidra. ® It is a solution-type eye drop that is easily and rapidly cleared by tears and then drained through the nasolacrimal duct, resulting in low intraocular bioavailability.

[0005] Currently, about 90% of the drugs used to treat ophthalmic diseases on the market are eye drops, with the remainder in ointments and gels. These drugs suffer from low bioavailability, poor patient compliance, and low utilization rate, resulting in unsatisfactory treatment effects on the eyes. Therefore, improving the bioavailability of drugs in the eye and achieving high drug loading and sustained-release are key to overcoming the barriers to drug treatment of dry eye.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The primary objective of this invention is to provide an soaking solution for corneal contact lenses. Since the material of the corneal contact lens itself is in a gel state, the water in the gel can interact with the water in the gel network of the corneal contact lens, thereby fully displacing the drug molecules in the soaking solution within the corneal contact lens. This allows the drug molecules to remain within the gel network, achieving a high drug loading capacity. Furthermore, the drug is slowly released into the eye through the corneal contact lens, directly acting on the eye to treat dry eye syndrome, while reducing toxic side effects.

[0008] The second objective of this invention is to provide a method for preparing an immersion solution for corneal contact lenses, which is simple to operate and operates under mild conditions.

[0009] The third objective of this invention is to provide a method for preparing a drug-release contact lens. The contact lens is soaked in an immersion solution, which allows drug molecules to remain in the contact lens, enabling it to have a high drug loading capacity while also allowing the drug molecules to be slowly released into the eye through the contact lens. This improves drug utilization, avoids high-concentration drug pulses into the eye, thereby reducing drug toxicity and side effects, and also solves the problem of not being able to administer eye drops while wearing contact lenses.

[0010] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0011] This invention provides an soaking solution for corneal contact lenses, which is mainly prepared from the following raw materials by weight percentage:

[0012] Listatin 0.01%-0.15%;

[0013] Buffer salt 0.1%-2%;

[0014] Sodium chloride 0.2%-1.2%;

[0015] Sodium thiosulfate 0-0.5%;

[0016] Pure water 97%-99%.

[0017] Preferably, as a further specific implementation,

[0018] Listatin 0.05%-0.1%;

[0019] Buffer salt content: 0.8%-1.6%;

[0020] Sodium chloride 0.4%-1.0%;

[0021] Sodium thiosulfate 0-0.3%;

[0022] Pure water 97%-98%.

[0023] Preferably, as a further specific implementation,

[0024] Listatin 0.08%;

[0025] Buffer salt 1.2%;

[0026] Sodium chloride 0.8%;

[0027] Sodium thiosulfate 0.2%;

[0028] Purified water 97.72%.

[0029] In the aforementioned raw materials, this invention dissolves ristatin in a buffer salt solution and uses sodium chloride to adjust the osmotic pressure of the soaking solution, maintaining it at a suitable osmotic pressure to avoid adverse effects on the eyes. The amount of each substance in the raw materials is crucial to this invention. Through a series of creative efforts, the inventors have obtained the most suitable ratio and amount of raw materials for the human eye. Specifically, the soaking solution prepared with the following proportions—ristatin 0.01%-0.15%; buffer salt 0.1%-2%; sodium chloride 0.2%-1.2%; sodium thiosulfate 0-0.5%; and purified water 97%-99%—preferably ristatin 0.05%-0.1%, buffer salt 0.8%-1.6%, sodium chloride 0.4%-1.0%, sodium thiosulfate 0-0.3%, and purified water 97%-98%—is highly effective. The soaking solution can interact with the water in the gel, thereby fully displacing the drug in the soaking solution within the gel network, allowing drug molecules to remain on the gel network and achieving a high drug loading capacity. In this invention, the soaking solution prepared with 0.05%-0.1% ritalostem has excellent effects. This is because if the amount of ritalostem added to the soaking solution is too high, a large number of ritalostem molecules will be loaded into the contact lens, destroying its network structure and causing swelling of the corneal contact lens, resulting in changes in the shape of the corneal contact lens and affecting its function. If the amount of ritalostem is too low, the amount of drug retained in the gel network will be too small to meet the medication requirements. To maintain the prepared soaking solution within a suitable pH range, ensuring it does not irritate the eyes while maximizing drug dissolution, a certain amount of buffer salt is added to achieve a stable pH range of 6-8. This minimizes irritation when the soaking solution comes into contact with the eye through the contact lens, reducing eye discomfort for the user. It also increases drug dissolution, allowing more drug molecules to be retained on the gel network of the contact lens, resulting in better therapeutic effects upon contact with the eye. Excessive addition of buffer salt can lead to an overly acidic or alkaline soaking solution, causing eye irritation and hindering drug dissolution; insufficient addition will result in incomplete drug dissolution and inadequate drug loading. Sodium chloride is used as an osmotic pressure regulator in this invention. Excessive addition of sodium chloride will lead to an excessively high osmotic pressure in the soaking solution, easily causing eye discomfort upon contact; insufficient addition will cause the contact lens to swell, altering its shape and affecting its function. Sodium thiosulfate, as the antioxidant of this invention, can effectively maintain the stability of the drug when it is within a suitable dosage range, making the drug molecules less susceptible to external environmental influences that could affect the drug's efficacy.

[0030] Preferably, as a further specific embodiment, the buffer salt is a mixture of boric acid and borax or a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0031] Preferably, as a further specific embodiment, the buffer salt is a mixture of boric acid and borax.

[0032] Preferably, as a further specific embodiment, the mass ratio of boric acid to borax is 1:(0.06-1.5).

[0033] Preferably, the mass ratio of boric acid to borax is 1:0.3.

[0034] The selection of the buffer salt is crucial to this invention. Preferably, the buffer salt is a mixture of boric acid and borax. This is because when the soaking solution comes into contact with the subsequent contact lens, some of the solution is carried into the eye. Therefore, the pH and osmotic pressure of the soaking solution are critical. Boric acid, as a mild and non-irritating disinfectant, is well-suited for corneal rinsing and cleaning, with minimal eye irritation. Its acidic nature, combined with borax, helps maintain the pH stability of the soaking solution, mitigating pH changes when other substances are added. Furthermore, the combined effect of both increases the solubility of listatin in the solution, maximizing its dissolution and increasing drug loading. This is because listatin... For litastazole, the pH of the solution is crucial for its dissolution. Litastazole has higher solubility under alkaline conditions. Therefore, to ensure the solution pH is within a suitable range, minimizes eye irritation, and does not affect the subsequent loading of litastazole into the gel network, this invention uses a mixture of boric acid and borax as a buffer salt. The optimal mass ratio of boric acid to borax is 1:(0.06-1.5), preferably 1:0.3. This results in the best soaking solution because when boric acid and borax are in a suitable mass ratio, the resulting solution pH is optimal for litastazole and subsequent operations, maximizing both litastazole solubility and drug loading. Furthermore, the buffer system formed by the mixture minimizes eye irritation. If boric acid is used in excess, the resulting buffer solution will be acidic, causing significant eye irritation and reducing the solubility of listatin in the solution. This also affects the subsequent exchange of water molecules between listatin and the gel, reducing drug loading and impacting therapeutic efficacy. Conversely, if boric acid is used in insufficient amounts, the resulting buffer solution will be alkaline, also causing significant eye irritation and affecting the drug's effectiveness. Similarly, if borax is used in excess, the resulting buffer solution will be too alkaline, causing significant eye irritation; conversely, if borax is used in insufficient amounts, the resulting buffer solution will be too acidic, affecting the solubility of listatin and reducing drug loading.

[0035] The present invention also provides a method for preparing an soaking solution for corneal contact lenses, comprising the following steps:

[0036] Add buffer salt, sodium chloride, sodium thiosulfate and purified water in sequence, and stir until well to obtain excipient solution;

[0037] Add listatin to the excipient solution, stir well, and then add purified water to obtain a mixture;

[0038] The mixture is then filtered and sterilized using a filter membrane to obtain the final product.

[0039] Preferably, as a further specific embodiment, the pore size of the filter membrane is 0.1 μm-0.45 μm;

[0040] Preferably, the pore size of the filter membrane is 0.2 μm.

[0041] In the preparation method of the soaking solution of the present invention, the pore size of the filter membrane is very important. This is because in the preparation process of the present invention, most of the bacteria and pyrogens present in the soaking solution are filtered by using the filter membrane. Therefore, when the pore size of the filter membrane is within a suitable range, most of the bacteria and pyrogens present in the soaking solution can be filtered out. In addition, a certain amount of undissolved raw materials will exist in the preparation process of the soaking solution. By using the filter membrane to filter them, it is avoided that the drug molecules in the soaking solution will be affected when they exchange with water molecules in the corneal contact lens.

[0042] This invention also provides a method for preparing a drug-release corneal contact lens, comprising the following steps:

[0043] Remove the corneal contact lens, immerse it in the soaking solution, seal it, and sterilize it.

[0044] In the preparation method of the drug-releasing contact lens of the present invention, the present invention prepares a drug-releasing contact lens by immersing the contact lens in an immersion solution, sealing and sterilizing it, so that the drug molecules are carried in the contact lens. By carrying the drug molecules in the contact lens in this way, the disadvantages of traditional eye drops, such as low bioavailability, high eye irritation and poor patient compliance, can be effectively avoided. By carrying the drug molecules in the contact lens, the contact lens can directly contact the eye. After wearing a contact lens, the user's tear film is divided into an in front of the lens and a behind it. The behind-the-lens tear film is only a few micrometers thick. The medication from the contact lens is released into both the in front and behind the lens simultaneously. Although the behind-the-lens tear film is very small, the significant difference in thickness and radius between it and the in front allows almost all the medication released from the contact lens to enter the cornea. This results in a lower drug concentration in the behind-the-lens tear film, creating a good drainage effect. The medication in the in front-the-lens tear film can be absorbed through the conjunctiva or drained through the lacrimal canaliculi. This method ensures that the ratio of drug molecules released into the tear film and the behind-the-lens tear film is close to 1:1, greatly improving bioavailability. In addition, most contact lenses are made of gel material, which has a certain sustained-release effect and can effectively avoid high-concentration drug pulses, thus reducing the toxic side effects of the drug. Furthermore, because the contact lens is made of gel material, when the contact lens is immersed in the soaking solution, the water in the gel interacts with the water molecules in the lens's mesh structure. This allows the drug molecules in the soaking solution to be displaced onto the contact lens. Since the pH and osmotic pressure of the soaking solution are within a suitable range, the drug molecules are retained as much as possible within the gel network and adsorbed onto the contact lens by van der Waals forces through hydrophilic chains. The addition of sodium thiosulfate prevents the drug molecules from being oxidized or damaged, thus preserving their efficacy. Ultimately, this achieves both high drug loading and sustained-release, allowing the drug to directly treat dry eye while correcting vision. Patients have good compliance, and there are few toxic side effects.In the preparation of drug-release contact lenses, the concentration of the soaking solution is crucial for this invention. When the contact lens is immersed in the soaking solution, a concentration of 0.1 mg / ml to 1.5 mg / ml, preferably 0.8 mg / ml, results in a superior contact lens. This is because when the soaking solution comes into contact with the contact lens, the drug molecules in the soaking solution replace the water molecules in the contact lens. If the concentration of the soaking solution is too high, the large concentration difference between the contact lens and the soaking solution will cause a large number of drug molecules to enter the gel structure, altering the morphology of the contact lens and affecting the therapeutic effect. Conversely, if the concentration of the soaking solution is too low, the amount of drug molecules loaded on the contact lens will be insufficient, resulting in a poor-performing contact lens.

[0045] In addition, corneal contact lenses are divided into rigid corneal contact lenses and soft corneal contact lenses. The latter mainly consists of two materials: hydrogel and silicone hydrogel. Both can be used as corneal contact lenses in this invention, including nelfilcon A, etafilcon A, narafilcon A, and senofilcon A.

[0046] Preferably, as a further specific embodiment, the sterilization conditions are: heating at 100°C for 8 hours to heating at 130°C for 6 minutes;

[0047] Preferably, the sterilization conditions are: a temperature of 115°C and a heating time of 2 hours.

[0048] In the preparation of the drug-release contact lens of this invention, the heating temperature and heating time for sterilization are crucial. Heating at 100°C for 8 hours to 130°C for 6 minutes, preferably 115°C for 2 hours, yields excellent drug-release contact lenses. This is because when the heating temperature is within the range provided by this invention, the sterilization effect achieved during contact between the contact lens and the soaking solution is better, while minimizing process impurities and making the prepared drug-release contact lens less susceptible to damage. If the heating temperature is too high and the heating time is too long, related process impurities will be generated, and the high temperature can easily damage the structure of the contact lens itself, preventing drug molecules from remaining in the gel network and thus affecting the drug loading. If the heating temperature is too low and the heating time is too short, sterilization will not be achieved, resulting in poor safety of the prepared contact lens.

[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0050] (1) The present invention provides an soaking solution for corneal contact lenses. Since the material of the corneal contact lens itself is in a gel state, the water in the gel can interact well with the water in the corneal contact lens gel network, thereby fully replacing the drug in the soaking solution in the corneal contact lens, so that the drug molecules are retained in the gel network, achieving the purpose of high drug loading, and the drug is slowly released into the eye through the corneal contact lens, achieving the purpose of directly acting on the eye to treat dry eye syndrome, reducing toxic side effects.

[0051] (2) The present invention provides a method for preparing an immersion solution for corneal contact lenses. The preparation method is simple to operate and the operating conditions are mild.

[0052] (3) The present invention provides a method for preparing a drug-releasing contact lens. The preparation method involves soaking the contact lens in an immersion solution, which allows the drug molecules to remain in the contact lens, enabling it to have a high drug loading capacity and also allowing the drug molecules to be slowly released into the eye through the contact lens. This improves the bioavailability of the drug while avoiding high concentrations of the drug pulsed into the eye, thereby reducing the toxic side effects of the drug. It also solves the problem of not being able to administer eye drops when wearing contact lenses. Detailed Implementation

[0053] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0054] To more clearly illustrate the technical solutions in this invention, specific embodiments are described below.

[0055] Example 1

[0056] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0057] The prescription, by weight percentage, is:

[0058]

[0059] The buffer salts are boric acid and borax, with a total mass of 1.608g;

[0060] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0061] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0062] Then, a filter membrane with a pore size of 0.1 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0063] Example 2

[0064] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0065] The prescription, by weight percentage, is:

[0066]

[0067] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of approximately 1:0.06 and a total mass of 1.3g.

[0068] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0069] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0070] Then, a filter membrane with a pore size of 0.45 μm was used to filter and sterilize the mixture to obtain the soaking solution. 1 ml of the soaking solution was poured into a glass bottle. Then, the corneal contact lens was taken out, and one corneal contact lens was placed in the glass bottle with tweezers. The bottle was sealed with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer membrane and then heated at 100℃ for 8 hours to obtain a drug-release corneal contact lens.

[0071] Example 3

[0072] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0073] The prescription, by weight percentage, is:

[0074]

[0075] The buffer salts are boric acid and borax, with a total mass of 1.883g.

[0076] Take a beaker and pour boric acid, borax, sodium sulfide, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0077] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0078] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0079] Example 4

[0080] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0081] The prescription, by weight percentage, is:

[0082]

[0083] The buffer salt is a mixture of boric acid and borax, with a total mass of 1.397g;

[0084] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0085] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0086] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 130℃ for 6 minutes to obtain a drug-release corneal contact lens.

[0087] Example 5

[0088] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0089] The prescription, by weight percentage, is:

[0090]

[0091] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of approximately 1:0.3 and a total mass of 1.608g.

[0092] Take a beaker and pour boric acid, borax, sodium chloride and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0093] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0094] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0095] Example 6

[0096] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0097] The prescription, by weight percentage, is:

[0098]

[0099] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of approximately 1:0.3 and a total mass of 1.608g.

[0100] Take a beaker and pour boric acid, borax, sodium chloride and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0101] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0102] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up the corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 124℃ for 18 minutes to obtain a drug-release corneal contact lens.

[0103] Example 7

[0104] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0105] The prescription, by weight percentage, is:

[0106]

[0107] The buffer salt is disodium hydrogen phosphate, with a mass of 0.363g;

[0108] Take a beaker and pour disodium hydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0109] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0110] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 121℃ for 15 minutes to obtain a drug-release corneal contact lens.

[0111] Example 8

[0112] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0113] The prescription, by weight percentage, is:

[0114]

[0115] The buffer salt is a mixture of sodium dihydrogen phosphate and sodium dihydrogen phosphate, with a total mass of 0.8g;

[0116] Take a beaker and pour disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0117] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0118] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0119] Example 9

[0120] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0121] The prescription, by weight percentage, is:

[0122]

[0123] The buffer salt is disodium hydrogen phosphate, with a mass of 0.1g;

[0124] Take a beaker and pour disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0125] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0126] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0127] Example 10

[0128] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0129] The prescription, by weight percentage, is:

[0130]

[0131] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of approximately 1:0.3, and a total mass of 0.81g.

[0132] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0133] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0134] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0135] Example 11

[0136] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0137] The prescription, by weight percentage, is:

[0138]

[0139] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of 1:0.3 and a total mass of 1.8g.

[0140] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0141] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0142] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0143] Example 12

[0144] The preparation process of the soaking solution used for corneal contact lenses is as follows:

[0145] The prescription, by weight percentage, is:

[0146]

[0147] The buffer salt is a mixture of boric acid and borax, with a mass ratio of boric acid to borax of 1:0.3 and a total mass of 1.2g.

[0148] Take a beaker and pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence. Stir with a stirring rod until the raw materials are completely dissolved to obtain the excipient solution.

[0149] Then, listatin was added to the excipient solution, and after stirring with a stirring rod, purified water was added and stirred evenly to obtain a mixture.

[0150] Then, a filter membrane with a pore size of 0.2 μm is used to filter and sterilize the mixture to obtain the soaking solution. Take a glass bottle, pour 1 ml of the soaking solution into the glass bottle, then take out the corneal contact lens, use tweezers to pick up one corneal contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and place it at a temperature of 115℃ for 2 hours to obtain a drug-release corneal contact lens.

[0151] Example 13

[0152] The specific preparation steps in this embodiment are the same as in Example 12, except that the mass ratio of boric acid and borax is adjusted to 1:0.1, that is, 1.09g of boric acid and 0.11g of borax.

[0153] Example 14

[0154] The specific preparation steps in this embodiment are the same as in Example 12, except that the mass ratio of boric acid and borax is adjusted to 1:0.4, that is, 0.70g of boric acid and 0.28g of borax.

[0155] Example 15

[0156] The specific preparation steps in this embodiment are the same as in Example 12, except that the buffer salt is changed from a mixture of boric acid and borax to a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate, wherein the mass of disodium hydrogen phosphate is 1g and the mass of sodium dihydrogen phosphate is 0.2g.

[0157] Example 16

[0158] The specific preparation steps in this embodiment are the same as in Example 12, except that the pore size of the filter membrane is 0.1 μm.

[0159] Example 17

[0160] The specific preparation steps in this embodiment are the same as in Example 12, except that the pore size of the filter membrane is 0.5 μm.

[0161] Example 18

[0162] The specific preparation steps in this embodiment are the same as in Example 12, except that the heating temperature is set to 100°C.

[0163] Example 19

[0164] The specific preparation steps in this embodiment are the same as in Example 12, except that the heating temperature is set to 130°C.

[0165] Example 20

[0166] The specific preparation steps in this embodiment are the same as in Example 12, except that the heating time is set to 1 hour.

[0167] Example 21

[0168] The specific preparation steps in this embodiment are the same as in Example 12, except that the heating time is set to 3 hours.

[0169] Comparative Example 1

[0170] The specific preparation steps in this embodiment are the same as in Example 12, except that borax is replaced with sodium hydroxide.

[0171] Comparative Example 2

[0172] The specific preparation steps in this embodiment are the same as in Example 12, except that boric acid is replaced with potassium dihydrogen phosphate.

[0173] Comparative Example 3

[0174] The specific preparation steps in this embodiment are the same as in Example 12, except that the prescription of the soaking solution is changed to 0.2g of rituximab, 1g of boric acid, 0.2g of borax, 0.8g of sodium chloride, 0.2g of sodium thiosulfate and 97.6g of purified water.

[0175] Comparative Example 4

[0176] The specific preparation steps in this embodiment are the same as in Example 12, except that the prescription of the soaking solution is changed to 0.08g of rituximab, 0.5g of boric acid, 0.2g of borax, 0.8g of sodium chloride, 0.2g of sodium thiosulfate and 98.2g of purified water.

[0177] Comparative Example 5

[0178] The specific preparation steps in this embodiment are the same as in Example 12, except that the prescription of the soaking solution is changed to 0.08g of rituximab, 1g of boric acid, 0.2g of borax, 1.5g of sodium chloride, 0.2g of sodium thiosulfate and 97.0g of purified water.

[0179] Comparative Example 6

[0180] The specific preparation steps in this embodiment are the same as in Example 12, except that the prescription of the soaking solution is changed to 0.08g of rituximab, 1g of boric acid, 0.2g of borax, 0.1g of sodium chloride, 0.2g of sodium thiosulfate and 98.4g of purified water.

[0181] Experimental Example 1: Measurement of Drug Release from Corneal Contact Lenses

[0182] The drug-releasing contact lenses prepared in Examples 1-20 and Comparative Examples 1-6 were tested. 50 ml of artificial tears was used as the release medium, and the temperature was 34°C. The in vitro release of the drug-releasing contact lenses was measured. Specifically, the drug-releasing contact lenses prepared according to this invention were placed in vials containing 50 ml of the release medium, sealed with rubber stoppers, and placed in an air bath constant-temperature shaker at 34°C and a shaking rate of 200 rpm. After 2 hours, samples were taken, injected into a high-performance liquid chromatograph (HPLC) for analysis, and the concentration of ristatin was calculated using the external standard method, followed by the calculation of its release amount.

[0183] The high-performance liquid chromatography (HPLC) conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; 0.05% trifluoroacetic acid-acetonitrile (60:40) was used as the mobile phase; the flow rate was 1.0 mL / min; the detection wavelength was 254 nm; the column temperature was 40 °C; and the injection volume was 30 μL. The final results are shown in Table 1 below.

[0184] Table 1

[0185]

[0186] Experiment Example 2: Determination of Corneal Contact Lens Swelling Rate

[0187] The corneal contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 were placed in deionized water to allow them to swell, and then weighed using a balance.

[0188] After weighing, dry it until its weight is constant, and then weigh it again using a balance.

[0189] Calculate the swelling ratio, where the swelling ratio = ;

[0190] The final results are shown in Table 1.

[0191] As can be seen from the table above, the drug-releasing contact lenses prepared by the method of the present invention do not swell after being soaked in the soaking solution, and the swelling rate is within a suitable range. However, in the comparative example, changing the amount of raw materials used in the present invention will cause some of the prepared contact lenses to change in shape, and the diameter will change significantly.

[0192] Experiment Example 3: Measurement of corneal contact lens transmittance

[0193] The transmittance of the corneal contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 was measured. The swollen drug-releasing soft corneal contact lenses were placed in a quartz dish, and their transmittance was measured in the visible light range (400-700 nm) using an ultraviolet spectrophotometer.

[0194] The final results are shown in Table 1.

[0195] Experimental Example: Determination of Drug Loading in Four Corneal Contact Lenses

[0196] The drug loading of the corneal contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 was determined using high-performance liquid chromatography (HPLC). The specific preparation steps are shown below:

[0197] Chromatographic conditions:

[0198] Column: Octadecylsilane-bonded silica gel as packing material; Detection wavelength: 254 nm; Column temperature: 40℃; Injection volume: 20 μL;

[0199] Mobile phase:

[0200]

[0201] Flow rate: 1.0 mL / min;

[0202] Test solution: Transfer the entire soaking solution of this product to a 100ml volumetric flask, add the mobile phase to the mark, mix well, and then accurately measure an appropriate amount to dilute with the mobile phase to a solution containing approximately 20µg of ristatin.

[0203] Reference solution: Accurately weigh ristatin, add an appropriate amount of mobile phase, sonicate to dissolve, and quantitatively dilute with mobile phase to prepare a solution containing approximately 20 µg of ristatin per ml.

[0204] The system suitability requirement is that the theoretical plate number of the reference solution, calculated based on the ristat peak, is not less than 3000.

[0205] Assay: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph, record the chromatogram, calculate the drug content in the soaking solution by peak area using the external standard method, and then calculate the drug content (drug loading) of each tablet using the following formula.

[0206]

[0207] In the formula:

[0208] This is the dosage, µg / tablet;

[0209] The peak area of ​​the test sample solution;

[0210] This represents the peak area of ​​the control solution;

[0211] The concentration of listatin in the control solution is in µg / ml;

[0212] The dilution factor of the test solution;

[0213] The final data is shown in Table 2 below:

[0214]

[0215] Therefore, based on the above experiments, it can be seen from the dosage of each raw material and the drug release data in Table 1, that the drug release of the corneal contact lenses prepared by the scheme of the present invention can reach more than 85% after 4 hours, as can be seen from the comparative examples 1-21 and 1-6. As can be seen from the experimental data in Tables 1 and 2, and through comparison with Example 12 and Comparative Examples 1-6, the amount of each substance in the raw materials of this invention is crucial. The inventors, through a series of creative efforts, have obtained the most suitable amounts of raw materials. Specifically, the prepared soaking solution contains: 0.01%-0.15% ristatin; 0.1%-2% buffer salt; 0.2%-1.2% sodium chloride; 0-0.5% sodium thiosulfate; and 97%-99% purified water. Preferably, the amounts are: 0.05%-0.1% ristatin, 0.8%-1.6% buffer salt, 0.4%-1.0% sodium chloride, 0-0.3% sodium thiosulfate, and 97%-98% purified water. Excellent performance is achieved in terms of swelling rate, light transmittance, drug release, and drug loading. The content of listatin in the raw materials of this invention is limited. From the swelling rate tables in Table 1 and the drug loading tables in Table 2, when the listatin content is between 0.01% and 0.15%, the prepared corneal contact lenses all achieve excellent results. However, as shown in Comparative Example 12 and Comparative Example 3, if the listatin content is outside the range provided by this invention, it will have a certain impact on the performance of the corneal contact lens. If the amount of listatin is too high, a large number of drug molecules enter the contact lens, leading to swelling and changes in the shape of the corneal contact lens, thus affecting the treatment effect during wear.

[0216] In the raw material dosage of this invention, sodium chloride, an osmotic pressure regulator, also has a certain influence on the corneal contact lens prepared by this invention. When the dosage of sodium chloride is between 0.2% and 1.2%, the corneal contact lens prepared has excellent performance. As can be seen from Comparative Examples 12 and 5-6, when sodium chloride is within a suitable range, the corneal contact lens prepared has excellent performance. As can be seen from Comparative Examples 12 and 5, if sodium chloride is added in excess, it will lead to excessively high osmotic pressure of the soaking solution, which can easily cause eye discomfort when in contact with the eye. As can be seen from the swelling rate in Table 1, as can be seen from Comparative Examples 12 and 6, if the dosage is too small, it will cause the corneal contact lens to swell and its shape will change, affecting the treatment effect.

[0217] Regarding the buffer salts used in this invention, the type and proportion of the selected buffer salts have a certain impact on the effect of the corneal contact lenses prepared by this invention. According to the drug loading data obtained in Table 2, comparing Examples 12 and 15 of this invention with Comparative Examples 1-2, it can be seen that in Examples 1 and 15 of this invention, when a mixture of boric acid and borax or a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate is selected as the buffer salt, the dissolution behavior is significantly better than that of the comparative examples. In Comparative Example 1, because the selected buffer salt is a mixture of sodium hydroxide and boric acid, the prepared drug solution is alkaline, which is more irritating to the eyes when worn. In Comparative Example 2, a mixture of potassium dihydrogen phosphate and borax is selected. At this time, the mixture of the two is acidic, and because the buffering capacity of the solution formed by the mixture of the two is not strong, the addition of listatin causes a drastic change in the pH of the solution, thereby reducing the solubility of listatin and making it impossible for listatin to dissolve in the solution. Therefore, the corneal contact lenses prepared according to the schemes of Comparative Examples 1 and 2 are not ideal. Therefore, for the present invention, the corneal contact lens prepared by using a mixture of boric acid and borax as a buffer salt exhibits excellent performance. This is because the pH of the solution is crucial for the dissolution of listatin, and its solubility is greater under alkaline conditions. Therefore, in order to maintain the pH of the solution within a suitable range that is gentle and non-irritating to the eyes, and to ensure that it does not affect the subsequent loading of listatin into the gel network, boric acid, as a gentle and non-irritating liquid, can be effectively used for corneal rinsing and cleaning with minimal irritation to the eyes. Furthermore, its acidity, combined with borax, helps maintain the pH stability of the soaking solution. Thus, adding a certain amount of other substances to the soaking solution can effectively slow down pH changes, ensuring that the solubility of listatin in the soaking solution is not affected. Therefore, the present invention maintains the soaking solution within a suitable acid-base range by adding a buffer salt, thereby preventing eye irritation while maximizing the dissolution of the drug in the soaking solution. Comparative examples 12-14 show that when the mass ratio of boric acid to borax is 1:(0.06-1.5), preferably 1:0.3, the resulting soaking solution is more ideal. This is because when boric acid and borax are in a suitable mass ratio, the pH of the solution after mixing allows ristatin to dissolve to the maximum extent without affecting subsequent operations. This maximizes the solubility of ristatin and better displaces it onto the corneal contact lens. Furthermore, the buffer system formed by the mixture of the two has less irritation to the eyes.If boric acid is used in excess, the resulting buffer solution will be acidic, causing significant eye irritation and reducing the solubility of listatin in the solution. This also affects the subsequent exchange of water molecules between listatin and the gel, reducing drug loading and impacting therapeutic efficacy. Conversely, if boric acid is used in insufficient amounts, the resulting buffer solution will be alkaline, also causing significant eye irritation and affecting the drug's effectiveness. Similarly, if borax is used in excess, the resulting buffer solution will be too alkaline, causing significant eye irritation; conversely, if borax is used in insufficient amounts, the resulting buffer solution will be too acidic, affecting the solubility of listatin and reducing drug loading.

[0218] In the preparation of the soaking solution, the pore size of the filter membrane has a certain impact on the effect of the prepared soaking solution. This is because there will be a certain amount of undissolved raw materials and small-diameter microorganisms in the preparation process of the soaking solution of the present invention. By using a filter membrane to filter them, the drug molecules in the soaking solution are not affected when they exchange with water molecules in the corneal contact lens, or the presence of microorganisms in the soaking solution may cause eye discomfort symptoms to the user.

[0219] During the preparation of the soaking solution, the heating temperature and heating time have a certain impact on the prepared corneal contact lenses. As shown in Table 2, comparing Examples 12 and 18-21 reveals that when the heating temperature and heating time are within a suitable range, the drug loading of the prepared corneal contact lenses is not significantly affected. This is because when the heating temperature is within the range provided by this invention, the bactericidal effect achieved in the contact between the corneal contact lens and the soaking solution is better, while minimizing process impurities and ensuring that the prepared drug-release corneal contact lenses are not damaged. If the heating temperature and time are not within the range provided by this invention, related degradation impurities will be generated, and the structure of the corneal contact lens itself is easily damaged at high temperatures, preventing drug molecules from remaining in the gel network, thus affecting the drug loading.

[0220] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An soaking solution for corneal contact lenses, characterized in that, It is mainly produced from the following raw materials by weight percentage: Listatin 0.01%-0.15%; Buffer salt 0.1%-2%; Sodium chloride 0.2%-1.2%; Sodium thiosulfate 0-0.5%; Pure water 97%-99%; The buffer salt is a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate or a mixture of boric acid and borax; The mass ratio of boric acid to borax is 1:(0.06-1.5).

2. The soaking solution according to claim 1, characterized in that, Listatin 0.05%-0.1%; Buffer salts: 0.8%-1.6%; Sodium chloride 0.4%-1.0%; Sodium thiosulfate 0-0.3%; Pure water 97%-98%.

3. The soaking solution according to claim 1, characterized in that, Listatin 0.08%; Buffer salt 1.2%; Sodium chloride 0.8%; Sodium thiosulfate 0.2%; Purified water 97.72%.

4. The soaking solution according to claim 1, characterized in that, Preferably, the mass ratio of boric acid to borax is 1:0.

3.

5. A method for preparing an soaking solution for corneal contact lenses as described in any one of claims 1-4, characterized in that, Includes the following steps: Add buffer salt, sodium chloride, sodium thiosulfate and purified water in sequence, and stir until well to obtain excipient solution; Add listatin to the excipient solution, stir well, and then add purified water to obtain a mixture; The mixture is then filtered and sterilized using a filter membrane to obtain the final product.

6. The preparation method according to claim 5, characterized in that, The pore size of the filter membrane is 0.1μm-0.45μm.

7. The preparation method according to claim 6, characterized in that, Preferably, the pore size of the filter membrane is 0.2 μm.

8. A method for preparing a drug-release corneal contact lens, characterized in that, The soaking solution prepared by the method of claim 5 includes the following steps: Remove the corneal contact lens, place it in the soaking solution, seal and sterilize.

9. The preparation method according to claim 8, characterized in that, The sterilization conditions are: heating at 100℃ for 8 hours to heating at 130℃ for 6 minutes.

10. The preparation method according to claim 9, characterized in that, Preferably, the sterilization conditions are: a temperature of 115°C and a heating time of 2 hours.

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