Soaking solution for corneal contact lens, preparation method and corneal contact lens

Abstract

The invention provides a soak solution for a corneal contact lens, a preparation method of the soak solution and the corneal contact lens, and the soak solution is mainly prepared from the following raw materials in percentage by mass: 0.01%-0.15% of litamilast, 0.01%-0.15% of sodium dodecyl benzene sulfonate, 0.01%-0.15% of sodium dodecyl benzene sulfonate and the balance of water. 0.1%-2% of buffer salt; 0.2%-1.2% of sodium chloride; 0-0.5% of sodium thiosulfate; and 97%-99% of purified water. The soak solution for the corneal contact lens prepared by the invention can well interact with water molecules in the corneal contact lens, so that drug molecules in the soak solution are well replaced in the corneal contact lens, and the drug molecules are retained in a gel network of the corneal contact lens; the bioavailability of the medicine is improved while high medicine loading capacity is realized, and the corneal contact lens prepared from the soak solution has the effect of slowly releasing the medicine, directly acts on eyes and can reduce the toxic and side effects of the medicine.

Description

Technical Field

[0001] The present invention relates to the technical field of corneal contact lenses, and in particular to an immersion liquid for corneal contact lenses, a preparation method and a corneal contact lens. Background Art

[0002] Eye health involves people of all ages and throughout the life cycle. Dry eye is the most common ocular surface disease in the world. Affected by changes in lifestyle and the widespread use of electronic products, the incidence of dry eye continues to rise. It is reported that the global incidence is about 5.5%-33.7%; the incidence of dry eye in my country is about 21%-30%, and there is a trend of younger age, which has become an important issue affecting the national eye health.

[0003] The rate of dry eye patients seeking medical treatment in China is low, and the available treatment options are limited. Currently, the most commonly used treatment options are artificial tears and immunosuppressants, and most patients fail to achieve satisfactory treatment results. The most commonly used anti-inflammatory drug for dry eye treatment worldwide is cyclosporine A ophthalmic emulsion Restasis. ® and lifitegrast eye drops Xiidra ® . And Xiidra ® Than Restasis ® It has a faster onset of effect. In two Phase III clinical trials, symptom improvement was observed within two weeks of taking the drug, while Restasis ® It usually takes 6 weeks of treatment to be effective, but 5%-25% of patients taking Xiidra ® Later, side effects such as irritation at the site of drug instillation, taste disturbance, and decreased vision may occur.

[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 cognate ligand intercellular adhesion molecule-1 (ICAM-1), interfering with the overexpression of ICAM-1 in the corneal and conjunctival tissues that causes dry eye. ® It is a solution-type eye drop, which is easily cleared by tears and then discharged through the nasolacrimal duct. The drug has low bioavailability in the eye.

[0005] Currently, about 90% of the drugs used to treat ophthalmic diseases on the market are eye drops, and the rest are in the form of ointments and gels. There are problems with low bioavailability and poor patient compliance, and the drug utilization rate is not high, and the therapeutic effect on the eye is unsatisfactory. Therefore, how to improve the bioavailability of drugs in the eye and achieve high drug loading and sustained-release drugs is the key to breaking through the barriers of drug treatment for dry eye.

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

[0007] The first purpose of the present invention is to provide an immersion solution for corneal contact lenses. Since the material of the corneal contact lenses is in a gel state, the water in the gel can interact with the water in the gel network of the corneal contact lenses, thereby fully replacing the drug molecules in the immersion solution in the corneal contact lenses, so that the drug molecules are retained in the gel network, achieving the purpose of high drug loading, and slowly releasing the drug to the eye through the corneal contact lenses, achieving the purpose of directly acting on the eye to treat dry eye syndrome, reducing toxic side effects.

[0008] The second object of the present invention is to provide a method for preparing an immersion solution for corneal contact lenses, which is simple to operate and has mild operating conditions.

[0009] The third purpose of the present invention is to provide a method for preparing a drug-releasing corneal contact lens, which uses an immersion liquid to soak the corneal contact lens so that the drug molecules can be retained in the corneal contact lens, so that it has a higher drug loading amount and can also slowly release the drug molecules in the eye through the corneal contact lens, thereby improving the drug utilization while avoiding high-concentration drug pulses in the eye, thereby reducing drug toxicity and side effects, and can also solve the problem of not being able to give eye drops when wearing corneal contact lenses.

[0010] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted: The present invention provides an immersion solution for corneal contact lenses, which is mainly prepared from the following raw materials in terms of mass percentage: Lifastat 0.01%-0.15%; Buffer salt 0.1%-2%; Sodium chloride 0.2%-1.2%; Sodium thiosulfate 0-0.5%; Purified water 97%-99%.

[0011] Preferably, as a further specific implementation, Lifastat 0.05%-0.1%; Buffer salt 0.8%-1.6%; Sodium chloride 0.4%-1.0%; Sodium thiosulfate 0-0.3%; Purified water 97%-98%.

[0012] Preferably, as a further specific implementation, Lifastat 0.08%; Buffer salt 1.2%; Sodium chloride 0.8%; Sodium thiosulfate 0.2%; Pure water 97.72%.

[0013] Among the above raw materials, the present invention dissolves lifalast in a buffered saline solution, and adjusts the osmotic pressure of the soaking solution by sodium chloride, so that it is maintained at a suitable osmotic pressure to avoid adverse effects on the eyes. Among the raw materials of the present invention, the amount of each substance is very important for the present invention. The inventor has obtained the raw materials and amounts most suitable for the human eye through a series of creative work, wherein according to lifalast 0.01%-0.15%; buffer salt 0.1%-2%; sodium chloride 0.2%-1.2%; sodium thiosulfate 0-0.5%; pure water 97%-99%, preferably lifalast 0.05%-0.1%, buffer salt 0.8%-1.6%, sodium chloride 0.4%-1.0%, sodium thiosulfate 0-0.3% and pure water 97%-98%, the prepared soaking solution has excellent effect, and the soaking solution can interact with the water in the gel, so as to fully replace the drug in the soaking solution in the gel network, so that the drug molecules can be retained on the gel network, and the purpose of high drug loading is achieved. In the present invention, when the dosage of lifalast is 0.05%-0.1%, the prepared immersion solution has excellent effect. This is because if the dosage of lifalast added to the immersion solution is too high, a large amount of lifalast molecules will be loaded into the contact lens to destroy its network structure, thereby causing the corneal contact lens to swell, causing the morphology of the corneal contact lens to change, and affecting the function of the corneal contact lens; if the dosage of lifalast is too small, the amount of drug retained in the gel network will be too small to meet the medication needs. In order to maintain the prepared immersion solution in a suitable acid-base range, the drug can be dissolved to the maximum extent without irritating the eye, so a certain amount of buffer salt is added to obtain a stable pH range of 6-8, so that the immersion solution is less irritating when it contacts the eye through the corneal contact lens, reducing the user's eye discomfort, and can increase the amount of drug dissolved, so that more drug molecules are retained on the gel network in the corneal contact lens as much as possible, so that it can have a better therapeutic effect when it contacts the eye. If the buffer salt is added in excess, the immersion solution will be too acidic or too alkaline, thereby irritating the eye and being unfavorable for the dissolution of the drug; if the amount is too small, the drug will not be fully dissolved, resulting in the drug loading not meeting the requirements. Sodium chloride is used as an osmotic pressure regulator of the present invention, so if sodium chloride is added in excess, the osmotic pressure of the immersion solution will be too high, which is easy to cause eye discomfort when contacting the eye; if the amount is too small, the corneal contact lens will swell, and its morphology will also change, affecting the contact lens function. Sodium thiosulfate is used as an antioxidant in the present invention. When it is in an appropriate dosage range, it can well maintain the stability of the drug and prevent the drug molecules from being easily affected by the external environment and thus affecting the medicinal effect.

[0014] 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.

[0015] Preferably, as a further specific embodiment, the buffer salt is a mixture of boric acid and borax.

[0016] Preferably, as a further specific embodiment, the mass ratio of the boric acid to borax is 1:(0.06-1.5); Preferably, the mass ratio of the boric acid to borax is 1:0.3.

[0017] Among them, the selection of the buffer salt of the present invention is very important for the present invention. For the present invention, it is preferred that the buffer salt is a mixture of boric acid and borax. This is because when the immersion solution contacts the subsequent corneal contact lens, a part of the immersion solution will be brought into the eye. Therefore, there are certain requirements for the pH and osmotic pressure of the immersion solution. Boric acid, as a mild and non-irritating disinfectant, can be well used for washing and cleaning the cornea. It is less irritating to the eye and is acidic. It can work together with borax to maintain the pH stability of the immersion solution, so that when a certain amount of other substances are added to the immersion solution, the change of pH is slowed down. The two work together to improve the solubility of lisdipamide in the solution, so that lisdipamide can be dissolved in the solution to the maximum extent, and the drug loading is increased. This is because for lisdipamide, For lisdenafil, the pH of the solution is the guarantee for the dissolution of lisdenafil, and its solubility is greater under alkaline conditions. Therefore, in order to make the pH of the solution in an appropriate range, and to reduce the irritation to the eyes, and not affect the subsequent loading of lisdenafil into the gel network, the present invention selects a mixture of boric acid and borax as a buffer salt, and selects a mass ratio of boric acid to borax of 1: (0.06-1.5), preferably 1: 0.3, the prepared immersion solution has the best effect. This is because when boric acid and borax are in an appropriate mass ratio, the solution pH that can be achieved after the two are mixed is the best for lisdenafil and subsequent operations, which can maximize the solubility of lisdenafil and the highest drug loading, and the buffer system formed by the mixture of the two is less irritating to the eyes. If the amount of boric acid is excessive, the buffer salt system formed by the mixture of the two will be acidic, which will cause greater irritation to the eyes and reduce the solubility of lisdapoxetine in the solution, and affect the subsequent replacement of lisdapoxetine with water molecules in the gel, reduce the drug loading, and affect the therapeutic effect; if the amount of boric acid is too small, the buffer salt system formed by the mixture of the two will be alkaline, which will cause greater irritation to the eyes and affect the medicinal effect. If the amount of borax is excessive, the buffer solution formed by the mixture of the two will be too alkaline, which will cause greater irritation to the eyes; and if the amount of borax is too small, the buffer solution formed by the mixture of the two will be too acidic, which will affect the solubility of lisdapoxetine, reduce the solubility of lisdapoxetine, and affect the drug loading.

[0018] The present invention also provides a method for preparing an immersion solution for corneal contact lenses, comprising the following steps: Add buffer salt, sodium chloride, sodium thiosulfate and purified water in sequence, and stir evenly to obtain an auxiliary material solution; Add lifalast to the auxiliary material solution, stir evenly, then add purified water to obtain a mixed solution; The mixed solution is filtered and sterilized using a filter membrane to obtain the product.

[0019] Preferably, as a further specific embodiment, the pore size of the filter membrane is 0.1 μm-0.45 μm; Preferably, the pore size of the filter membrane is 0.2 μm.

[0020] In the preparation method of the soaking liquid of the present invention, the pore size of the filter membrane is very important for the present invention. This is because in the preparation process of the present invention, most of the bacteria and pyrogens present in the soaking liquid are filtered through the filter membrane. Therefore, when the pore size of the filter membrane is within an appropriate range, most of the bacteria and pyrogens present in the soaking liquid can be filtered out. In addition, there will be a certain amount of undissolved raw materials in the soaking liquid during the preparation process. By filtering them through the filter membrane, the drug molecules in the subsequent soaking liquid are not affected when they are replaced with water molecules in the corneal contact lens.

[0021] The present invention also provides a method for preparing a drug-releasing corneal contact lens, comprising the following steps: Take out the corneal contact lens, put it into the soaking solution, seal it and sterilize it.

[0022] In the preparation method of the drug-releasing corneal contact lens of the present invention, the present invention prepares a drug-releasing corneal contact lens by immersing the corneal contact lens in an immersion solution, sealing and then sterilizing so that the drug molecules are carried in the corneal contact lens. By carrying the drug molecules in the corneal contact lens in this way, the disadvantages of low bioavailability, high eye irritation and poor patient compliance brought about by traditional eye drops can be well avoided. The corneal contact lens is loaded with drug molecules, so that the corneal contact lens is in direct contact with the eye. After wearing contact lenses, the user's tear film is divided into the tear film in front of the lens and the tear film behind the lens. The thickness of the tear film behind the lens is only a few microns. The drugs in the contact lenses are released to the tear film in front of the lens and the tear film behind the lens at the same time. Although the volume of the tear film behind the lens is very small, due to the huge difference in thickness and radius between the tear film behind the lens and the tear film in front of the lens, almost all the drugs released from the contact lenses can enter the cornea, making the drug concentration in the tear film behind the lens low, thus forming a good leakage state, while the drugs in the tear film in front of the lens can be absorbed by the conjunctiva or discharged through the lacrimal canaliculi. In this way, the ratio of drug molecules released into the tear film and the tear film behind the lens can be close to 1:1, which greatly improves the bioavailability. In addition, most contact lenses are made of gel materials, which have a certain sustained release effect and can well avoid high-concentration pulses of drugs, thereby reducing the toxic and side effects of drugs. And because the corneal contact lens is made of gel material, when the corneal contact lens is immersed in the immersion solution, since the gel itself is a grid structure, when the corneal contact lens is immersed in the drug solution, the water in the gel will interact with the water molecules in the corneal contact lens grid, so that the drug molecules in the immersion solution are replaced on the corneal contact lens, and because the pH and osmotic pressure of the immersion solution are both in an appropriate range, the drug molecules in the immersion solution can be retained in the gel network as much as possible, and adsorbed on the corneal contact lens by the van der Waals force with the hydrophilic chain, and because of the addition of sodium thiosulfate, the drug molecules are not oxidized, so that they are not damaged and thus affect the medicinal effect, and finally a high drug loading amount can be achieved while also achieving the purpose of sustained release of the drug, so that it can directly act on the eye to treat dry eye while correcting vision, and the patient compliance is good and the toxic and side effects are small.When preparing drug-releasing corneal contact lenses, the concentration of the immersion solution is very important for the present invention. When the corneal contact lens is placed in the immersion solution, the concentration of the immersion solution is 0.1 mg / ml-1.5 mg / ml, preferably 0.8 mg / ml, and the corneal contact lens prepared therefrom has excellent effects. This is because when the immersion solution contacts the corneal contact lens to achieve the replacement of the drug molecules in the immersion solution with the water molecules in the corneal contact lens, if the concentration of the immersion solution is too high, due to the high concentration difference between the corneal contact lens and the immersion solution, a large number of drug molecules enter the gel structure, the morphology of the corneal contact lens changes, and thus the treatment effect is affected; and if the solubility of the immersion solution is too low, the drug molecules carried on the corneal contact lens will be insufficient, the drug loading amount will not meet the requirements, and the prepared corneal contact lens will have poor effects.

[0023] In addition, corneal contact lenses are divided into hard corneal contact lenses and soft corneal contact lenses. The latter are mainly made of two materials: hydrogel and silicone hydrogel, both of which can be selected as corneal contact lenses in the present invention, including nelfilcon A, etafilconA, narafilcon A and senofilcon A.

[0024] Preferably, as a further specific embodiment, the sterilization conditions are: heating at 100°C for 8h to 130°C for 6 minutes; Preferably, the sterilization conditions are: temperature of 115° C. and heating time of 2 h.

[0025] In the preparation process of the drug-releasing contact lens of the present invention, the heating temperature and heating time of the sterilization conditions are very important for the present invention. When the heating temperature is 100°C for 8h to 130°C for 6 minutes, preferably the heating temperature is 115°C and the heating time is 2h, the prepared drug-releasing contact lens has excellent effect. This is because when the heating temperature is within the range provided by the present invention, it can achieve a better sterilization effect in the contact between the contact lens and the immersion liquid, while also minimizing the process impurities produced, and can make the prepared drug-releasing 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 structure of the contact lens itself will be easily destroyed under high temperature conditions, so that the drug molecules cannot be retained in the gel network, thereby affecting the drug loading; if the heating temperature is too low and the heating time is too short, the sterilization effect cannot be achieved, so that the safety of the prepared contact lens is poor.

[0026] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention provides an immersion solution for corneal contact lenses. Since the material of the corneal contact lenses is in a gel state, the water in the gel can interact well with the water in the gel network of the corneal contact lenses, thereby fully replacing the drug in the immersion solution in the corneal contact lenses, so that the drug molecules are retained in the gel network, thereby achieving the purpose of high drug loading, and the drug is slowly released into the eye through the corneal contact lenses, thereby achieving the purpose of directly acting on the eye to treat dry eye syndrome, and reducing toxic side effects.

[0027] (2) The present invention provides a method for preparing an immersion solution for corneal contact lenses. The preparation method is simple to operate and has mild operating conditions.

[0028] (3) The present invention provides a method for preparing a drug-releasing contact lens, wherein the contact lens is soaked in an immersion solution so that the drug molecules can be retained in the contact lens, thereby having a higher drug loading capacity and being able to slowly release the drug molecules into the eye through the contact lens, thereby improving the bioavailability of the drug while avoiding high concentration pulses of the drug in the eye, thereby reducing the drug's toxic side effects, and also solving the problem of not being able to administer eye drops when wearing contact lenses. DETAILED DESCRIPTION

[0029] The technical solution of the present invention will be clearly and completely described below in conjunction with specific implementation methods, but those skilled in the art will understand that the embodiments described below are part of the embodiments of the present invention, rather than all of the 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 ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0030] In order to more clearly explain the technical solution of the present invention, it is described in the form of specific embodiments below.

[0031] Example 1 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0032] The buffer salts are boric acid and borax, with a total mass of 1.608 g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.1 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0033] Example 2 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0034] The buffer salt is a mixture of boric acid and borax, wherein the mass ratio of boric acid to borax is approximately 1:0.06, and the total mass is 1.3 g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.45 μm to filter and sterilize the mixed solution to obtain an immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 100°C for 8 hours to obtain a drug-releasing contact lens.

[0035] Example 3 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0036] The buffer salts are boric acid and borax, with a total mass of 1.883 g; Take a beaker, pour boric acid, borax, sodium sulfide, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0037] Example 4 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0038] The buffer salt is a mixture of boric acid and borax, with a total mass of 1.397 g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain an immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 130°C for 6 minutes to obtain a drug-releasing contact lens.

[0039] Example 5 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0040] The buffer salt is a mixture of boric acid and borax, wherein the mass ratio of boric acid to borax is about 1:0.3, and the total mass is 1.608g; Take a beaker, pour boric acid, borax, sodium chloride and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0041] Example 6 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0042] The buffer salt is a mixture of boric acid and borax, wherein the mass ratio of boric acid to borax is about 1:0.3, and the total mass is 1.608g; Take a beaker, pour boric acid, borax, sodium chloride and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain an immersion solution; take a glass bottle, pour the immersion solution into the glass bottle, then take out the corneal contact lens, use tweezers to clamp the corneal contact lens and put it into the glass bottle, seal and roll the cap with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, and heat it at 124°C for 18 minutes to obtain a drug-releasing corneal contact lens.

[0043] Example 7 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0044] The buffer salt is disodium hydrogen phosphate, with a mass of 0.363 g; Take a beaker, pour disodium hydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain an immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 121°C for 15 minutes to obtain a drug-releasing contact lens.

[0045] Example 8 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0046] The buffer salt is a mixture of sodium dihydrogen phosphate and sodium dihydrogen phosphate, with a total mass of 0.8 g; Take a beaker, pour disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0047] Example 9 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0048] The buffer salt is disodium hydrogen phosphate, with a mass of 0.1 g; Take a beaker, pour disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0049] Example 10 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0050] The buffer salt is a mixture of boric acid and borax, and the mass ratio of boric acid to borax is approximately 1:0.3, with a total mass of 0.81 g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0051] Embodiment 11 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0052] The buffer salt is a mixture of boric acid and borax, and the mass ratio of boric acid to borax is 1:0.3, and the total mass is 1.8g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0053] Example 12 The preparation process of the immersion solution for corneal contact lenses is as follows: In terms of mass percentage, the prescription is:

[0054] The buffer salt is a mixture of boric acid and borax, and the mass ratio of boric acid to borax is 1:0.3, and the total mass is 1.2g; Take a beaker, pour boric acid, borax, sodium chloride, sodium thiosulfate and purified water into the beaker in sequence, and stir with a stirring rod until the raw materials are completely dissolved to obtain an auxiliary material solution; Then, lifalast was added to the auxiliary material solution, and purified water was added after stirring with a stirring rod again, and the mixture was stirred evenly to obtain a mixed solution; Then, use a filter membrane with a pore size of 0.2 μm to filter and sterilize the mixed solution to obtain the immersion solution; take a glass bottle, pour 1 ml of the immersion solution into the glass bottle, then take out the contact lens, use tweezers to grab a contact lens and put it into the glass bottle, seal it with a chlorobutyl rubber stopper covered with a polytetrafluoroethylene / ethylene copolymer film, roll the cap, and heat it at 115°C for 2 hours to obtain the drug-releasing contact lens.

[0055] Example 13 The specific preparation steps of this example are the same as those of Example 12, except that the mass ratio of boric acid to borax is adjusted to 1:0.1, i.e., 1.09 g of boric acid and 0.11 g of borax.

[0056] Embodiment 14 The specific preparation steps of this example are the same as those of Example 12, except that the mass ratio of boric acid to borax is adjusted to 1:0.4, i.e., 0.70 g of boric acid and 0.28 g of borax.

[0057] Embodiment 15 The specific preparation steps of this embodiment are consistent with those of Example 12, except that the buffer salt is adjusted 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 1 g and the mass of sodium dihydrogen phosphate is 0.2 g.

[0058] Example 16 The specific preparation steps of this embodiment are consistent with those of Embodiment 12, except that the pore size of the filter membrane is set to 0.1 μm.

[0059] Embodiment 17 The specific preparation steps of this embodiment are consistent with those of Embodiment 12, except that the pore size of the filter membrane is set to 0.5 μm.

[0060] Embodiment 18 The specific preparation steps of this embodiment are consistent with those of Embodiment 12, except that the heating temperature is set to 100°C.

[0061] Embodiment 19 The specific preparation steps of this embodiment are consistent with those of Embodiment 12, except that the heating temperature is set to 130°C.

[0062] Embodiment 20 The specific preparation steps of this embodiment are consistent with those of Embodiment 12, except that the heating time is set to 1 hour.

[0063] Embodiment 21 The specific preparation steps of this embodiment are consistent with those of Example 12, except that the heating time is set to 3 hours.

[0064] Comparative Example 1 The specific preparation steps of this embodiment are the same as those of Example 12, except that borax is replaced by sodium hydroxide.

[0065] Comparative Example 2 The specific preparation steps of this example are the same as those of Example 12, except that boric acid is replaced by potassium dihydrogen phosphate.

[0066] Comparative Example 3 The specific preparation steps of this example are consistent with those of Example 12, except that the prescription of the soaking solution is changed to 0.2 g of lifilamid, 1 g of boric acid, 0.2 g of borax, 0.8 g of sodium chloride, 0.2 g of sodium thiosulfate and 97.6 g of purified water.

[0067] Comparative Example 4 The specific preparation steps of this example are consistent with those of Example 12, except that the prescription of the soaking solution is changed to 0.08 g of lifalast, 0.5 g of boric acid, 0.2 g of borax, 0.8 g of sodium chloride, 0.2 g of sodium thiosulfate and 98.22 g of purified water.

[0068] Comparative Example 5 The specific preparation steps of this example are consistent with those of Example 12, except that the prescription of the soaking solution is changed to 0.08 g of lifilamid, 1 g of boric acid, 0.2 g of borax, 1.5 g of sodium chloride, 0.2 g of sodium thiosulfate and 97.02 g of purified water.

[0069] Comparative Example 6 The specific preparation steps of this example are consistent with those of Example 12, except that the prescription of the soaking solution is changed to 0.08 g of lifilamid, 1 g of boric acid, 0.2 g of borax, 0.1 g of sodium chloride, 0.2 g of sodium thiosulfate and 98.42 g of purified water.

[0070] Experimental Example 1 Determination of drug release from contact lenses The drug-releasing contact lenses prepared in Examples 1-20 and Comparative Examples 1-6 were measured, and 50 ml of artificial tears were used as the release medium at a temperature of 34° C. to measure the in vitro release of the drug-releasing contact lenses. The specific method is as follows: the drug-releasing contact lenses prepared in the present invention are placed in a vial with 50 ml of the release medium, sealed with a rubber stopper, and placed in an air bath constant temperature oscillator, the temperature is set to 34° C., the oscillation rate is 200 rpm, and samples are taken after 2 hours, injected into a high performance liquid chromatograph for measurement, and the concentration of lifalast is calculated according to the external standard method, and then the release amount is calculated.

[0071] The conditions of high performance liquid chromatography are as follows: octadecylsilane bonded silica gel as filler, 0.05% trifluoroacetic acid-acetonitrile (60:40) as mobile phase; flow rate 1.0 ml per minute; detection wavelength 254 nm; column temperature 40°C; injection volume 30 μL. The final results are shown in Table 1 below.

[0072] Table 1

[0073] Experimental Example 2: Measurement of Swelling Rate of Contact Lenses The contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 were placed in deionized water to allow the contact lenses to swell, and then weighed using a balance; After weighing, dry it until the weight is constant and weigh it again with a balance; Calculate the swelling ratio, where swelling ratio = ; The final results are shown in Table 1.

[0074] It can be seen from the above table that the drug-releasing corneal contact lens prepared by the scheme of the present invention does not swell after being soaked in the soaking solution, and the swelling rate is within an appropriate range. However, in the comparative example, when the amount of the raw materials of the present invention is changed, the morphology of a part of the prepared corneal contact lenses changes, and the diameter changes significantly.

[0075] Experimental Example 3 Measurement of light transmittance of corneal contact lenses The light transmittance of the contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 was measured. The swollen drug-releasing soft contact lenses were placed in a quartz dish, and their light transmittance was measured in the visible light range (400-700 nm) using an ultraviolet spectrophotometer.

[0076] The final results are shown in Table 1.

[0077] Experimental Example Determination of drug loading in quadratic contact lenses The corneal contact lenses prepared in Examples 1-21 and Comparative Examples 1-6 were tested for drug loading using high performance liquid chromatography. The specific preparation steps are as follows: Chromatographic conditions: Chromatographic column: octadecylsilane bonded silica as filler; detection wavelength: 254nm; column temperature: 40℃; injection volume: 20uL; Mobile Phase:

[0078] Flow rate: 1.0 mL / min; Test solution: Transfer all the soaking solution of this product to a 100 ml volumetric flask, add mobile phase to the mark, mix well, and then accurately measure an appropriate amount and dilute it with mobile phase to a solution containing approximately 20 µg of lisdenafil.

[0079] Reference solution: Take lifalast, weigh accurately, add appropriate amount of mobile phase, sonicate to dissolve, and quantitatively dilute with mobile phase to make a solution containing about 20 µg of lifalast per 1 ml.

[0080] System suitability requires that the theoretical plate number of the reference solution calculated based on the ritahist peak be no less than 3000.

[0081] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph, record the chromatogram, calculate the drug content in the immersion solution by the peak area according to the external standard method, and then calculate the drug content (drug loading) of each tablet according to the following formula.

[0082]

[0083] Where: is the dosage, µg / tablet; is the peak area of ​​the test solution; is the peak area of ​​the control solution; is the concentration of lifalast in the control solution, µg / ml; Dilution factor of the test solution; The final data is shown in Table 2 below:

[0084] Therefore, it can be seen from the above experiments that, in terms of the dosage of each raw material, it can be seen from the drug release data in Table 1, and by comparing Examples 1-21 and Comparative Examples 1-6, it can be seen that the drug release of the corneal contact lenses prepared by the scheme of the present invention can reach more than 85% at 4 hours. It can be seen from the experimental data in Table 1 and Table 2, and from the comparison of Example 12 and Comparative Examples 1-6, in the raw materials of the present invention, the amount of each substance is very important for the present invention. The inventors have obtained the most suitable raw material dosage through a series of creative work, wherein according to 0.01%-0.15% of lifalast; 0.1%-2% of buffer salt; 0.2%-1.2% of sodium chloride; 0-0.5% of sodium thiosulfate; 97%-99% of pure water, preferably 0.05%-0.1% of lifalast, 0.8%-1.6% of buffer salt, 0.4%-1.0% of sodium chloride, 0-0.3% of sodium thiosulfate and 97%-98% of pure water, the prepared soaking liquid has the effect of The present invention is excellent, and the swelling rate, light transmittance, drug release and drug loading can all reach a good range. Among the raw materials of the present invention, the content of lifalast is limited to a certain extent. From the swelling rate in Table 1 and the drug loading table in Table 2, when lifalast is in the range of 0.01%-0.15%, the prepared corneal contact lenses can achieve excellent effects. By comparing Example 12 and Comparative Example 3, it can be seen that if the content of lifalast is not in the range provided by the present invention, it will have a certain impact on the performance of the corneal contact lens. If the dosage of lifalast is too high, a large amount of drug molecules enter the contact lens, thereby causing the corneal contact lens to swell, causing the morphology of the corneal contact lens to change, which affects the therapeutic effect when worn.

[0085] Among the raw material dosages of the present invention, the osmotic pressure regulator sodium chloride also has a certain effect on the corneal contact lens prepared by the present invention. When the dosage of sodium chloride is 0.2%-1.2%, the corneal contact lens prepared therefrom has excellent effect. By comparing Example 12 with Comparative Examples 5-6, it can be seen that when sodium chloride is in an appropriate range, the corneal contact lens prepared therefrom has excellent effect. By comparing Example 12 with Comparative Example 5, it can be seen that if excessive sodium chloride is added, the osmotic pressure of the immersion solution will be too high, which is easy to cause eye discomfort when in contact with the eyes; from the swelling rate in Table 1, it can be seen by comparing Example 12 with Comparative Example 6 that if the dosage is too small, the corneal contact lens will swell and its morphology will also change, affecting the treatment effect.

[0086] As for the buffer salt used in the present invention, the type of buffer salt selected and the dosage ratio have a certain influence on the effect of the corneal contact lens prepared by the present invention. According to the drug loading data obtained in Table 2, it can be seen from the comparison of Example 12, Example 15 and Comparative Examples 1-2 of the present invention that when the buffer salt is selected as a mixture of boric acid and borax or a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate in Example 1 and Example 15 of the present invention, the dissolution behavior is significantly better than that of the comparative example, and in Comparative Example 1, since 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; while in Comparative Example 2, a mixture of potassium dihydrogen phosphate and borax is selected, and the mixture of the two is acidic at this time, and the buffering capacity of the solution formed by the mixture of the two is not strong, so when lifalast is added, the pH of the solution changes drastically, thereby reducing the solubility of lifalast, so that lifalast cannot be dissolved in the solution. Therefore, the effect of the corneal contact lens prepared according to the schemes of Comparative Examples 1 and 2 is not ideal. Therefore, for the present invention, when a mixture of boric acid and borax is selected as a buffer salt, the performance of the prepared corneal contact lens is excellent. This is because for lisdopamine, the pH of the solution is a guarantee for lisdopamine to dissolve in the solution, and its solubility is greater under alkaline conditions. Therefore, in order to make the pH of the solution within an appropriate range and be mild and non-irritating to the eyes, it will not affect the subsequent loading of lisdopamine into the gel network. Boric acid, as a mild and non-irritating liquid, can be used for washing and cleaning the cornea when used in the eyes. It has minimal irritation to the eyes, and it is acidic. It can work with borax to maintain the pH stability of the soaking solution. Therefore, when a certain amount of other substances are added to the soaking solution, the change of pH can be well slowed down, so that the solubility of lisdopamine in the soaking solution is not affected. Therefore, the present invention maintains the soaking solution within an appropriate acid-base range by adding a buffer salt, so that it does not irritate the eyes and can also allow the drug to be dissolved in the soaking solution to the maximum extent. By comparing Examples 12-14, it can be seen that when the mass ratio of boric acid to borax is 1:(0.06-1.5), preferably 1:0.3, the immersion solution prepared is more ideal. This is because when boric acid and borax are in an appropriate mass ratio, the solution pH that can be achieved after the two are mixed can make lifalast dissolve in the solution to the greatest extent and will not affect subsequent operations. It can maximize the solubility of lifalast and better replace lifalast on the corneal contact lens, and the buffer system formed by the mixture of the two is less irritating to the eyes.If the amount of boric acid is excessive, the buffer salt system formed by the mixture of the two will be acidic, which will cause greater irritation to the eyes and reduce the solubility of lisdapoxetine in the solution, and affect the subsequent replacement of lisdapoxetine with water molecules in the gel, reduce the drug loading, and affect the therapeutic effect; if the amount of boric acid is too small, the buffer salt system formed by the mixture of the two will be alkaline, which will cause greater irritation to the eyes and affect the medicinal effect. If the amount of borax is excessive, the buffer solution formed by the mixture of the two will be too alkaline and cause greater irritation to the eyes; and if the amount of borax is too small, the buffer solution formed by the mixture of the two will be too acidic, affecting the solubility of lisdapoxetine, reducing the solubility of lisdapoxetine and affecting the drug loading.

[0087] During the preparation of the soaking liquid, the pore size of the filter membrane has a certain influence on the effect of the prepared soaking liquid. This is because a certain amount of undissolved raw materials and microorganisms with smaller diameters will exist in the preparation process of the soaking liquid of the present invention. By using a filter membrane to filter them, it is possible to avoid the drug molecules in the subsequent soaking liquid being affected when they are replaced with water molecules in the corneal contact lens, or the presence of microorganisms in the soaking liquid causing symptoms of eye discomfort to the user.

[0088] In the process of preparing the soaking liquid, the heating temperature and heating time have a certain influence on the prepared corneal contact lens. It can be seen from the drug loading data in Table 2 that by comparing Example 12 and Example 18-21, when the heating temperature and heating time are in an appropriate range, the drug loading of the prepared corneal contact lens is not significantly affected. This is because when the heating temperature is in the range provided by the present invention, it can achieve a better sterilization effect in the contact between the corneal contact lens and the soaking liquid, and can also minimize the process impurities produced, and can make the prepared drug-releasing corneal contact lens not damaged. If the heating temperature and time are not in the range provided by the present invention, related degradation impurities will be generated, and the structure of the corneal contact lens itself is easily destroyed under high temperature conditions, so that the drug molecules cannot be retained in the gel network, thereby affecting the drug loading.

[0089] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements 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. A soaking solution for corneal contact lenses, characterized in that: In terms of mass percentage, it is mainly made from the following raw materials: Lifastat 0.01%-0.15%; Buffer salt 0.1%-2%; Sodium chloride 0.2%-1.2%; Sodium thiosulfate 0-0.5%; Purified water 97%-99%.

2. The soaking liquid according to claim 1, characterized in that Lifastat 0.05%-0.1%; Buffer salt 0.8%-1.6%; Sodium chloride 0.4%-1.0%; Sodium thiosulfate 0-0.3%; Purified water 97%-98%.

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

4. The soaking liquid according to claim 1, characterized in that The buffer salt is a mixture of boric acid and borax or a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate.

5. The soaking liquid according to claim 4, characterized in that The buffer salt is a mixture of boric acid and borax.

6. The soaking liquid according to claim 5, characterized in that The mass ratio of the boric acid to borax is 1:(0.06-1.5); Preferably, the mass ratio of the boric acid to borax is 1:0.

3.

7. A method for preparing an immersion solution for corneal contact lenses according to any one of claims 1 to 6, characterized in that: The following steps are involved: Add buffer salt, sodium chloride, sodium thiosulfate and purified water in sequence, and stir evenly to obtain an auxiliary material solution; Add lifalast to the auxiliary material solution, stir evenly, then add purified water to obtain a mixed solution; The mixed solution is filtered and sterilized using a filter membrane to obtain the product.

8. The preparation method according to claim 7, characterized in that: The pore size of the filter membrane is 0.1 μm-0.45 μm; Preferably, the pore size of the filter membrane is 0.2 μm.

9. A method for preparing a drug-releasing corneal contact lens, characterized in that: The soaking liquid prepared by the preparation method of claim 7 comprises the following steps: Take out the corneal contact lens, put it into the immersion solution, seal it and sterilize it.

10. The preparation method according to claim 9, characterized in that: The sterilization conditions are: heating at 100°C for 8h to 130°C for 6min; Preferably, the sterilization conditions are: temperature of 115° C. and heating time of 2 h.

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