Special eye moistening liquid for silicone hydrogel contact lenses for relieving xerophthalmia and preparation method of eye moistening liquid

Abstract

The invention belongs to the technical field of ophthalmic care products, and discloses a silica hydrogel eye lotion special for contact lenses and capable of relieving xerophthalmia and a preparation method of the silica hydrogel eye lotion. The eye moistening liquid disclosed by the invention is prepared from the following components: 0.2 to 0.8 percent of sodium hyaluronate, 0.8 to 2.0 percent of trehalose, 0.1 to 0.3 percent of polyglutamic acid, 0.3 to 1.05 percent of a lubricating agent, 0.08 to 0.3 percent of a taurine-hyaluronic acid conjugate, 0.01 to 0.03 percent of rosmarinic acid, 0.0005 to 0.002 percent of vitamin B12, 0.1 to 0.3 percent of a buffering agent, 0.5 to 1.0 percent of an osmotic pressure regulator, 0.1 to 0.2 percent of a preservative, 0.1 to 0.5 percent of a solubilizer and the balance of water. The eye moistening liquid provided by the invention comprehensively improves the tear film stability, ocular surface protection and lens compatibility, and is especially suitable for patients with moderate and severe xerophthalmia.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of ophthalmic care products, in particular to a special eye drop for silicone hydrogel contact lenses for relieving dry eye and a preparation method thereof. BACKGROUND

[0002] With the change of modern lifestyle, people spend more time using electronic devices, and combined with environmental pollution and other factors, the incidence of dry eye is on the rise. At the same time, more and more people choose to wear contact lenses to correct vision. Silicone hydrogel contact lenses are widely favored due to their high oxygen permeability. However, wearing contact lenses, especially for a long time, can further exacerbate eye dryness, affecting eye comfort and health.

[0003] There are many types of eye drops on the market, but relatively few products are specifically designed for silicone hydrogel contact lenses and can effectively relieve dry eye. Some existing eye drops have poor moisturizing effect, strong irritating ingredients, and poor compatibility with silicone hydrogel materials. For example, although some eye drops can temporarily relieve eye dryness, the duration is short and frequent use is required; some eye drops can affect the performance of silicone hydrogel contact lenses when in contact, such as reducing oxygen permeability and causing lens deformation. Therefore, it is of great practical significance to develop a special eye drop that can effectively relieve dry eye symptoms and is well adapted to silicone hydrogel contact lenses. SUMMARY

[0004] The present application aims to provide a special eye drop for silicone hydrogel contact lenses for relieving dry eye and a preparation method thereof, which can effectively improve eye dryness symptoms through a multi-level efficacy system, provide long-lasting moisturizing effect, enhance compatibility with silicone hydrogel contact lenses, and have mild and non-irritating ingredients, as well as nutrition repair and protection functions.

[0005] To achieve the above-mentioned application purposes, the present application provides the following technical solutions: The present application provides a special eye drop for silicone hydrogel contact lenses for relieving dry eye, which comprises the following components by mass fraction: Sodium hyaluronate 0.2-0.8%, trehalose 0.8-2.0%, polyglutamic acid 0.1-0.3%, lubricant 0.3-1.05%, taurine-hyaluronic acid conjugate 0.08-0.3%, rosemary acid 0.01-0.03%, vitamin B12 0.0005-0.002%, buffer 0.1-0.3%, osmotic pressure regulator 0.5-1.0%, preservative 0.1-0.2%, solubilizer 0.1-0.5%, and the balance is water.

[0006] Further, in the one special eye drop for silicon hydrogel contact lenses for alleviating dry eye syndrome, the sodium hyaluronate includes a mixture of low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate and high molecular weight sodium hyaluronate. The low molecular weight sodium hyaluronate has a molecular weight of 100,000-800,000; the medium molecular weight sodium hyaluronate has a molecular weight of 800,000-1,300,000; and the high molecular weight sodium hyaluronate has a molecular weight of 1,800,000-2,200,000. The mass ratio of the low molecular weight sodium hyaluronate, the medium molecular weight sodium hyaluronate and the high molecular weight sodium hyaluronate is 1:0.5-0.7:0.2-0.4.

[0007] Further, in the one special eye drop for silicon hydrogel contact lenses for alleviating dry eye syndrome, the lubricant includes hydroxyethyl cellulose-polyvinyl alcohol graft copolymer and polydimethylsiloxane-polyether copolymer; the mass fraction of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer in the eye drop is 0.25-0.9%; and the mass fraction of the polydimethylsiloxane-polyether copolymer in the eye drop is 0.05-0.15%.

[0008] Further, in the one special eye drop for silicon hydrogel contact lenses for alleviating dry eye syndrome, the preparation method of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer includes the following steps: mixing hydroxyethyl cellulose, polyvinyl alcohol, initiator and water under a protective atmosphere, adjusting pH to 5.5-6.5, and performing copolymerization reaction; and adding a terminating agent after the reaction to obtain the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer. The mass ratio of the hydroxyethyl cellulose and the polyvinyl alcohol is 1-3:1; the mass of the initiator is 0.5-1.5% of the total mass of the hydroxyethyl cellulose and the polyvinyl alcohol; and the copolymerization reaction conditions include a temperature of 65-80°C and a time of 2-4h. The preparation method of the polydimethylsiloxane-polyether copolymer includes the following steps: mixing hydrogen-terminated polydimethylsiloxane, allyl polyethylene glycol, inhibitor, catalyst and toluene under a protective atmosphere, and performing addition reaction to obtain the polydimethylsiloxane-polyether copolymer. The mass ratio of the hydrogen-terminated polydimethylsiloxane and the allyl polyethylene glycol is 1:0.7-1.0; the catalyst is a Karstedt catalyst; the amount of the catalyst is 0.01-0.05% of the total mass of the hydrogen-terminated polydimethylsiloxane and the allyl polyethylene glycol, based on the mass of Pt in the catalyst; and the addition reaction conditions include a temperature of 70-85°C and a time of 3-5h.

[0009] Further, in the silicon hydrogel contact lens special eye drops for relieving dry eye, the preparation method of the taurine-hyaluronic acid conjugate comprises the following steps: mixing the activated taurine, sodium hyaluronate and water under a protective atmosphere, performing a coupling reaction, dialysis, freeze-drying, and obtaining the taurine-hyaluronic acid conjugate. The molar ratio of the taurine to the sodium hyaluronate used in the activated taurine is 6-9:1; the coupling reaction conditions include that the pH is 5-6, the temperature is 30-45 DEG C, and the time is 18-30 h.

[0010] Further, in the silicon hydrogel contact lens special eye drops for relieving dry eye, the buffer is a boric acid-borax buffer.

[0011] Further, in the silicon hydrogel contact lens special eye drops for relieving dry eye, the osmotic pressure regulator is sodium chloride.

[0012] Further, in the silicon hydrogel contact lens special eye drops for relieving dry eye, the preservative is potassium sorbate.

[0013] Further, in the silicon hydrogel contact lens special eye drops for relieving dry eye, the solubilizing agent is hydroxypropyl-beta-cyclodextrin.

[0014] The application further provides a preparation method of the silicon hydrogel contact lens special eye drops for relieving dry eye, comprising the following steps: Mixing water with a total mass of 70% of water, a buffer, an osmotic pressure regulator and a preservative to obtain a first mixed solution; Mixing water with a total mass of 10% of water, a solubilizing agent and rosmarinic acid to obtain a second mixed solution; Mixing water with a total mass of 5% of water and taurine-hyaluronic acid conjugate to obtain a third mixed solution; Mixing water with a total mass of 0.5% of water and vitamin B12 to obtain a fourth mixed solution; Mixing water with a total mass of 8% of water and a lubricant to obtain a fifth mixed solution; Mixing the first mixed solution and the second mixed solution, adding sodium hyaluronate, polyglutamic acid and trehalose, and then mixing the third mixed solution, the fourth mixed solution, the fifth mixed solution and the remaining water to obtain the silicon hydrogel contact lens special eye drops for relieving dry eye.

[0015] Compared with the prior art, the application has the following beneficial effects: (1) Strong and long-lasting moisturizing lubrication: The formulation of the present application uses low, medium and high molecular weight sodium hyaluronate (HA), which forms a synergistic effect. High molecular weight HA forms a long-acting moisturizing film on the ocular surface, reducing water evaporation; medium molecular weight HA provides good viscoelasticity and residence time; low molecular weight HA has better penetration, deeply nourishing corneal epithelial cells, meeting the needs of instant moisturizing to long-acting water locking. Trehalose as a natural compatible osmoprotectant stabilizes the lipid layer of the tear film, protects the corneal epithelial cells from high osmotic pressure and dry damage, and enhances the survival ability of cells in a dry environment. Polyglutamic acid has strong moisture absorption and water retention capacity, can absorb a large amount of water, and significantly improve the moisturizing performance of the solution, prolong the wetting effect.

[0016] (2) The present application uses two lubricants, hydroxyethyl cellulose-polyvinyl alcohol graft copolymer combines the thickening and adhesion of cellulose and the film-forming lubricity of polyvinyl alcohol, forming a smooth, hydrophilic and long-lasting protective film on the ocular surface and lens surface, reducing friction and improving wearing comfort. The polydimethylsiloxane-polyether copolymer is specially designed for the hydrophobic surface of silicone hydrogel lenses. The siloxane part has good compatibility with the lens material, can effectively spread and reduce the surface tension of the lens; the polyether part provides excellent hydrophilic lubricity. This "anchoring-lubricating" structure greatly improves the wettability of the lens surface, reduces the dry feeling caused by protein and lipid deposition. In addition, taurine-hyaluronic acid conjugate combines the cell penetration regulation, antioxidant, and cell membrane stabilization functions of taurine and the moisturizing and lubricating properties of hyaluronic acid, has a longer ocular surface residence time, and provides synergistic moisturizing and cell protection. The overall formulation of the present application avoids components that are prone to adsorption or reaction with silicone hydrogel materials (such as some cationic polymers, high-concentration ionic surfactants), reducing the risk of lens parameter changes or sediment accumulation.

[0017] (3) Anti-inflammatory, antioxidant and corneal repair: The present application adds rosmarinic acid, which is a potent natural polyphenolic antioxidant and anti-inflammatory agent, can effectively scavenge free radicals, inhibit the production of inflammatory factors, reduce the ocular surface inflammatory response accompanying dry eye, and relieve eye redness, burning and other discomfort. The present application also adds vitamin B12, which can participate in cell metabolism, promote the repair and regeneration of corneal and conjunctival epithelial cells, and help the recovery of damaged ocular surface tissue. Taurine (in conjugate) has anti-inflammatory, cell membrane stabilizing and osmotic pressure regulating effects, protecting corneal epithelial cells from high osmotic pressure and inflammatory damage. Trehalose can protect cells from oxidative stress and dry damage by stabilizing cell membranes and proteins.

[0018] (4) Tear film stability and ocular surface protection: macromolecular components such as HA, graft copolymer, etc. help to increase the viscoelasticity of the tear fluid, prolong the tear film break-up time, and improve the stability of the tear film. The protective film formed by the lubricant reduces the mechanical friction damage between the lens and the eyelid, cornea. Anti-inflammatory and antioxidant components protect the ocular surface microenvironment and promote the formation of a healthy tear film.

[0019] (5) High safety: The present application selects preservatives (potassium sorbate) and solubilizers (hydroxypropyl-β-cyclodextrin) that are mild and widely used in ophthalmic preparations. The boric acid-borax buffer system provides a stable and near-physiological tear fluid pH environment. Osmotic pressure regulators (NaCl) ensure that the solution is isotonic with the tear fluid. The concentrations of each component are controlled within the safe and effective range.

[0020] (6) The present application uses a step-by-step mixing preparation method (especially first dissolving the buffer salt, osmotic pressure regulator and preservative to establish a stable base solution; separately handling the solubilized rosmarinic acid, conjugate, vitamin B12 and lubricant) to ensure that each component is fully dissolved, uniformly dispersed, and to avoid possible incompatibility or degradation (such as vitamin B12 is sensitive to light and pH). This is crucial for maintaining the activity of macromolecular polymers (HA, graft copolymer, etc.) and functional components (rosmarinic acid, taurine conjugate). DETAILED DESCRIPTION

[0021] The present application provides a kind of to alleviate dry eye silicon hydrogel contact lens special eye drops, comprising the following mass fraction of components: Sodium hyaluronate 0.2~0.8%, trehalose 0.8~2.0%, polyglutamic acid 0.1~0.3%, lubricant 0.3~1.05%, taurine-hyaluronic acid conjugate 0.08~0.3%, rosmarinic acid 0.01~0.03%, vitamin B12 0.0005~0.002%, buffer 0.1~0.3%, osmotic pressure regulator 0.5~1.0%, preservative 0.1~0.2%, solubilizer 0.1~0.5%, the rest is water.

[0022] In the present application, the sodium hyaluronate preferably includes a mixture of low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate and high molecular weight sodium hyaluronate.

[0023] In the present application, the molecular weight of the low molecular weight sodium hyaluronate is preferably 100-800 thousand.

[0024] In the present application, the molecular weight of the medium molecular weight sodium hyaluronate is preferably 800-1300 thousand.

[0025] In the present application, the molecular weight of the high molecular weight sodium hyaluronate is preferably 1800-2200 thousand.

[0026] In this invention, the mass ratio of the low molecular weight sodium hyaluronate, the medium molecular weight sodium hyaluronate, and the high molecular weight sodium hyaluronate is preferably 1:0.5~0.7:0.2~0.4, more preferably 1:0.55~0.65:0.25~0.35, and even more preferably 1:0.6:0.3.

[0027] In this invention, the lubricant preferably comprises hydroxyethyl cellulose-polyvinyl alcohol graft copolymer and polydimethylsiloxane-polyether copolymer.

[0028] In this invention, the mass fraction of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer in the eye drops is preferably 0.25-0.9%, more preferably 0.4-0.75%, and even more preferably 0.55%.

[0029] In this invention, the preparation method of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer includes the following steps: under a protective atmosphere, hydroxyethyl cellulose, polyvinyl alcohol, initiator and water are mixed, the pH is adjusted to 5.5~6.5, and a copolymerization reaction is carried out; after the reaction is completed, a terminator is added to obtain the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer.

[0030] In this invention, the hydroxyethyl cellulose and the polyvinyl alcohol are preferably purified before the reaction.

[0031] In this invention, the molecular weight of the hydroxyethyl cellulose is preferably 50,000 to 100,000.

[0032] In this invention, the degree of polymerization of the polyvinyl alcohol is preferably 1700-2000, and the degree of hydrolysis is preferably 98-99%.

[0033] In this invention, the mass ratio of the hydroxyethyl cellulose to the polyvinyl alcohol is preferably 1 to 3:1, more preferably 1.5 to 2.5:1, and even more preferably 2:1.

[0034] In this invention, the initiator is preferably ammonium persulfate.

[0035] In this invention, the mass of the initiator is preferably 0.5-1.5% of the total mass of hydroxyethyl cellulose and polyvinyl alcohol, more preferably 0.8-1.2%, and even more preferably 1.0%.

[0036] In this invention, the preferred method of "mixing hydroxyethyl cellulose, polyvinyl alcohol, initiator and water, and adjusting the pH to 5.5-6.5" is as follows: mixing hydroxyethyl cellulose, polyvinyl alcohol and water, adjusting the pH to 5.5-6.5, and then adding the aqueous solution of the initiator to the aforementioned mixed solution.

[0037] In this invention, the conditions for mixing the hydroxyethyl cellulose, polyvinyl alcohol and water include: a temperature preferably of 45~55°C, more preferably of 48~52°C, and even more preferably of 50°C; and a time preferably of 15~45 min, more preferably of 25~35 min, and even more preferably of 30 min.

[0038] In this invention, the solid content of the mixed solution after the hydroxyethyl cellulose, polyvinyl alcohol and water are mixed is preferably 5-8%, more preferably 5-7%, and even more preferably 6%.

[0039] In this invention, the conditions for the copolymerization reaction include: a temperature of 65~80℃, more preferably 65~75℃, and more preferably 70℃; and a time of 2~4h, more preferably 2.5~3.5h, and more preferably 3h.

[0040] In this invention, the terminator is preferably hydroquinone.

[0041] In this invention, the amount of the terminating agent added is preferably 0.05-0.3% of the total mass of hydroxyethyl cellulose and polyvinyl alcohol, more preferably 0.1-0.25%, and even more preferably 0.2%.

[0042] In this invention, the mixing time after adding the terminator is preferably 15-45 min, more preferably 25-35 min, and even more preferably 30 min.

[0043] In this invention, the separation and purification of the product after adding the terminator includes: mixing the reaction solution with anhydrous ethanol to precipitate the precipitate, allowing it to stand and then filtering it, washing it with 70% ethanol solution, filtering it, drying it, and passing it through an 80-mesh sieve.

[0044] In this invention, other conditions in the preparation method of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer are not limited, and methods well known in the art can be used.

[0045] In this invention, the mass fraction of the polydimethylsiloxane-polyether copolymer in the eye drops is preferably 0.05-0.15%, more preferably 0.10-0.15%, and even more preferably 0.15%.

[0046] In this invention, the preparation method of the polydimethylsiloxane-polyether copolymer includes the following steps: under a protective atmosphere, hydrogen-terminated polydimethylsiloxane, allyl polyethylene glycol, inhibitor, catalyst and toluene are mixed and subjected to an addition reaction to obtain the polydimethylsiloxane-polyether copolymer.

[0047] In this invention, the molecular weight of the hydrogen-terminated polydimethylsiloxane is preferably 2000-5000, and the Si-H content is preferably 0.1-0.3 mmol / g.

[0048] In this invention, the molecular weight of the allyl polyethylene glycol is preferably 1000-3000, and the double bond content is preferably 98%.

[0049] In this invention, the mass ratio of the hydrogen-terminated polydimethylsiloxane to the allyl polyethylene glycol is preferably 1:0.7~1.0, more preferably 1:0.7~0.9, and even more preferably 1:0.8.

[0050] In this invention, the inhibitor is preferably tetramethyltetravinylcyclotetrasiloxane.

[0051] In this invention, the amount of the inhibitor is preferably 0.2-0.8% of the total mass of hydrogen-terminated polydimethylsiloxane and allyl polyethylene glycol, more preferably 0.3-0.7%, and even more preferably 0.5%.

[0052] In this invention, the catalyst is preferably a cassette catalyst.

[0053] In this invention, the amount of catalyst used is preferably 0.01 to 0.05% of the total mass of hydrogen-terminated polydimethylsiloxane and allyl polyethylene glycol, more preferably 0.03 to 0.05%, and even more preferably 0.04%, based on the mass of Pt in the catalyst.

[0054] In this invention, the preferred method for mixing the hydrogen-capped polydimethylsiloxane, allyl polyethylene glycol, inhibitor, catalyst, and toluene is as follows: the hydrogen-capped polydimethylsiloxane is mixed with toluene, and allyl polyethylene glycol is added to obtain a mixed raw material solution; the inhibitor and catalyst are added sequentially thereto.

[0055] In this invention, the solid content of the mixed raw material solution is preferably 15-20%, more preferably 15-17%, and even more preferably 16%.

[0056] In this invention, the conditions for the addition reaction include: a temperature preferably of 70-85°C, more preferably of 75-80°C, and even more preferably of 80°C; and a time preferably of 3-5 hours, more preferably of 3.5-4.5 hours, and even more preferably of 4 hours.

[0057] In this invention, the product is preferably purified after the addition reaction, including: after the reaction is completed, cooling to room temperature, removing toluene and unreacted impurities by vacuum distillation; dissolving the residue in dichloromethane, mixing with anhydrous ethanol to precipitate, allowing to stand and then filtering; washing the filter cake with 70% ethanol aqueous solution, filtering and vacuum drying.

[0058] In this invention, other conditions in the preparation method of the polydimethylsiloxane-polyether copolymer are not limited, and methods well known in the art can be used.

[0059] In this invention, the preparation method of the taurine-hyaluronic acid conjugate includes the following steps: under a protective atmosphere, activated taurine, sodium hyaluronate and water are mixed to carry out a coupling reaction, dialyzed and freeze-dried to obtain the taurine-hyaluronic acid conjugate.

[0060] In this invention, the molecular weight of the sodium hyaluronate is preferably 50-80 kDa.

[0061] In this invention, the activation method of taurine includes: mixing taurine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide and phosphate buffer to carry out the activation reaction.

[0062] In this invention, the molar ratio of taurine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and N-hydroxysuccinimide is preferably 3~5:4~6:4~6, more preferably 3.5~4.5:4.5~5.5:4.5~5.5, and even more preferably 4:5:5.

[0063] In this invention, the activation reaction conditions include: the temperature is preferably room temperature; the time is preferably 1 to 3 hours, more preferably 1.5 to 2.5 hours, and even more preferably 2 hours.

[0064] In this invention, the molar ratio of taurine used in the activated taurine to sodium hyaluronate is preferably 6 to 9:1, more preferably 7 to 9:1, and even more preferably 8:1.

[0065] In this invention, the conditions for the coupling reaction include: pH preferably 5-6, more preferably 6; temperature preferably 30-45°C, more preferably 35-45°C, more preferably 40°C; and time preferably 18-30h, more preferably 22-26h, more preferably 24h.

[0066] In this invention, the dialysis conditions include: the dialysate is preferably a 0.1 mol / L NaCl solution; the molecular weight cutoff of the dialysis bag is preferably 3.5 kDa; and the dialysis time is preferably 2 to 4 days, more preferably 2 to 3 days, and even more preferably 3 days.

[0067] In this invention, filtration is preferably performed after dialysis.

[0068] In this invention, other conditions in the preparation method of the taurine-hyaluronic acid conjugate are not limited, and methods well known in the art can be used.

[0069] In this invention, the buffer is preferably a boric acid-borax buffer solution.

[0070] In this invention, the osmotic pressure regulator is preferably sodium chloride.

[0071] In this invention, the preservative is preferably potassium sorbate.

[0072] In this invention, the solubilizer is preferably hydroxypropyl-β-cyclodextrin.

[0073] In this invention, the mass fraction of sodium hyaluronate is 0.2-0.8%, preferably 0.3-0.5%, and more preferably 0.4%.

[0074] In this invention, the mass fraction of trehalose is 0.8-2.0%, preferably 1.0-1.5%, and more preferably 1.2%.

[0075] In this invention, the mass fraction of the polyglutamic acid is 0.1-0.3%, preferably 0.15-0.25%, and more preferably 0.2%.

[0076] In this invention, the mass fraction of the lubricant is 0.3~1.05%, preferably 0.5~0.9%, and more preferably 0.7%.

[0077] In this invention, the mass fraction of the taurine-hyaluronic acid coupling compound is 0.08-0.3%, preferably 0.1-0.25%, and more preferably 0.15%.

[0078] In this invention, the mass fraction of rosmarinic acid is 0.01~0.03%, preferably 0.015~0.025%, and more preferably 0.02%.

[0079] In this invention, the mass fraction of vitamin B12 is 0.0005~0.002%, preferably 0.0008~0.0015%, and more preferably 0.001%.

[0080] In this invention, the mass fraction of the buffer is 0.1-0.3%, preferably 0.15-0.25%, and more preferably 0.2%.

[0081] In this invention, the mass fraction of the osmotic pressure regulator is 0.5-1.0%, preferably 0.7-0.9%, and more preferably 0.8%.

[0082] In this invention, the preservative has a mass fraction of 0.1-0.2%, preferably 0.12-0.18%, and more preferably 0.15%.

[0083] In this invention, the mass fraction of the solubilizer is 0.1-0.5%, preferably 0.2-0.4%, and more preferably 0.3%.

[0084] In this invention, unless otherwise specified, the protective atmosphere used is preferably nitrogen.

[0085] This invention also provides a method for preparing a silicone hydrogel contact lens lubricating solution to relieve dry eye syndrome, comprising the following steps: Mix 70% of the total mass of water, buffer, osmotic pressure regulator and preservative to obtain the first mixture; Mix and homogenize 10% of the total mass of water, solubilizer, and rosmarinic acid to obtain a second mixture; A third mixture was obtained by mixing 5% of the total mass of water with the taurine-hyaluronic acid coupling agent. Mix 0.5% of the total mass of water with vitamin B12 to obtain the fourth mixture; Mix 8% of the total mass of water with lubricant to obtain the fifth mixture; The first and second mixtures are combined, and sodium hyaluronate, polyglutamic acid, and trehalose are added and mixed. Then, the third, fourth, and fifth mixtures are added and mixed with the remaining water to obtain a silicone hydrogel contact lens lubricating solution.

[0086] In this invention, the conditions for mixing 70% of the total mass of water, buffer, osmotic pressure regulator and preservative include: preferably a temperature of 40~50℃ and a time of ≥30min.

[0087] In this invention, the conditions for mixing and homogenizing include: a rotation speed preferably of 5000~20000 rpm, more preferably of 8000~12000 rpm, and even more preferably of 10000 rpm; and a time preferably of 3~10 min, more preferably of 4~7 min, and even more preferably of 5 min.

[0088] In this invention, the mixing rate of the fifth mixture is preferably ≤150 rpm.

[0089] In this invention, vacuum defoaming is performed before obtaining the eye drops.

[0090] In this invention, other parameters and conditions in the preparation method are not limited, and solutions well known in the art can be used.

[0091] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. 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.

[0092] Preparation Example 1

[0093] This preparation example provides a method for preparing the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer, polydimethylsiloxane-polyether copolymer, and taurine-hyaluronic acid coupling compound in Examples 1-3 and Comparative Examples 1-3.

[0094] The preparation method of hydroxyethyl cellulose-polyvinyl alcohol graft copolymer includes the following steps: (1) Raw material pretreatment Hydroxyethyl cellulose (HEC) purification: Weigh 10g HEC (molecular weight of 50,000 to 100,000, Shenzhen Youpuhui Pharmaceutical Co., Ltd.), add 100mL of deionized water, stir at 50℃ until completely dissolved (mass concentration 10%), filter with a 0.45μm filter membrane to remove insoluble impurities, dry the filtrate under vacuum at 40℃ to constant weight, pulverize and set aside; Polyvinyl alcohol (PVA) purification: Weigh 10g PVA (degree of polymerization 1800, degree of alcoholysis 98%, Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.), add 100mL deionized water, stir at 80℃ until completely dissolved (mass concentration 10%), filter to remove impurities, vacuum dry (40℃), and pulverize for later use; (2) Add 200 mL of deionized water to a four-necked reactor and purge with nitrogen (flow rate 50 mL / min) for 15 min to remove oxygen; weigh the pretreated HEC and PVA according to the mass ratio HEC:PVA = 2:1, add them to the reactor in sequence, stir at 50 °C for 30 min until completely dissolved to form a homogeneous aqueous solution (total solid content 6%); adjust the pH of the system to 6.0 with 0.1 mol / L hydrochloric acid; raise the temperature to 70 °C, maintain a nitrogen atmosphere, and slowly add ammonium persulfate (APS, pre-dissolved in 20 mL of deionized water) at a mass fraction of 1.0% of the total mass of raw materials to the reactor (dropping time 30 min). After the addition of 0.2 wt% hydroquinone, the reaction was stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and 0.2 wt% hydroquinone was added and stirred for 30 minutes to quench residual free radicals. The reaction solution was slowly poured into 3 times the volume of anhydrous ethanol (with magnetic stirring), and a white flocculent precipitate was formed. After standing for 1 hour, the precipitate was filtered and the filter cake was collected. The filter cake was washed 3 times with 70% ethanol solution to remove unreacted HEC, PVA homopolymer and residual initiator. The purified product was then filtered to obtain the purified product. The purified product was placed in a vacuum drying oven and dried at 45°C for 12 hours to constant weight. After pulverizing, the product was passed through an 80-mesh sieve to obtain the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer.

[0095] The preparation method of polydimethylsiloxane-polyether copolymer includes the following steps: (1) Raw material pretreatment Dehydration of hydrogen-terminated polydimethylsiloxane (PDMS-H): Weigh 20g of PDMS-H (molecular weight 2000~5000, Si-H content 0.2mmol / g, Jiangsu Runfeng Synthetic Technology Co., Ltd.), add 50mL of anhydrous toluene, stir at 60℃ for 30min to dissolve, add 5g of 3Å molecular sieve, let stand for 24h to dehydrate, filter to remove molecular sieve for later use; Purification of allyl polyethylene glycol: Weigh 15g of allyl polyethylene glycol (molecular weight 1000~3000, double bond content 98%, Shanghai Mairui Biochemical Technology Co., Ltd.), filter it with a 0.45μm filter membrane to remove mechanical impurities, and vacuum dry (40℃, 2h) to remove water for later use. (2) Add the dehydrated PDMS-H toluene solution to a three-necked flask, purge with nitrogen (flow rate 30 mL / min) for 15 min to remove oxygen; add purified allyl polyethylene glycol, controlling the mass ratio of PDMS-H to allyl polyethylene glycol to be 1:0.8, stir until completely dissolved (solid content of the system 16%), add 0.5 wt% of the inhibitor tetramethyltetravinylcyclotetrasiloxane to suppress side reactions, and continue purging with nitrogen for 10 min; raise the temperature to 70 °C, and under nitrogen protection, slowly add the caster catalyst (0.04% of the total mass of raw materials based on Pt, Wuhan Kemike Biomedical Technology Co., Ltd.), adding dropwise... The reaction time was 30 min to avoid excessive local catalyst concentration leading to crosslinking. After the addition was complete, the temperature was raised to 80℃ and kept at that temperature for 4 h. After the reaction was completed, the mixture was cooled to room temperature and distilled under reduced pressure (60℃, vacuum degree 0.09MPa) to remove toluene and unreacted small molecule impurities. The residue was dissolved in a small amount of dichloromethane (mass ratio 1:5) and slowly poured into 5 times the volume of anhydrous ethanol (with magnetic stirring). A white flocculent precipitate was formed and allowed to stand for 2 h before being filtered. The filter cake was washed 3 times with 70% ethanol aqueous solution to remove free PEG and unreacted PDMS. After filtration, it was dried under vacuum at 45℃ for 12 h to obtain polydimethylsiloxane-polyether copolymer.

[0096] The preparation method of taurine-hyaluronic acid conjugate includes the following steps: (1) Taurine activation: Taurine (16 mmol) was dissolved in 50 mL of phosphate buffer (pH=5.5), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20 mmol, EDC) and N-hydroxysuccinimide (20 mmol, NHS) were added. The mixture was stirred at 25 °C for 2 h to activate the carboxyl group of taurine to form an active ester. (2) The reaction system was protected by nitrogen. HA (2.5 mmol repeat unit, molecular weight 50~80kDa, purity >95%, Xi'an Zebang Biotechnology Co., Ltd.) was dissolved in 100mL of ultrapure water. The activated taurine solution was added dropwise to adjust the pH to 6.0 and reacted at 40℃ for 24h. The reaction solution was dialyzed with 0.1mol / L NaCl solution for 3 days (the solution was changed 3 times a day). The molecular weight cutoff of the dialysis bag was 3.5kDa to remove unreacted taurine and EDC / NHS byproducts. The dialysis solution was filtered through a 0.22μm filter membrane for sterilization and freeze-dried to obtain taurine-hyaluronic acid conjugate.

[0097] Example 1

[0098] This embodiment provides a silicone hydrogel contact lens eye drops for relieving dry eye syndrome, comprising the following components by mass fraction: Sodium hyaluronate 0.4%, trehalose 1.2%, polyglutamic acid 0.2%, lubricant 0.7% (hydroxyethyl cellulose-polyvinyl alcohol graft copolymer 0.55%, polydimethylsiloxane-polyether copolymer 0.15%), taurine-hyaluronic acid coupling agent 0.15%, rosmarinic acid 0.02%, vitamin B12 0.001%, boric acid-borax buffer 0.2%, sodium chloride 0.8%, potassium sorbate 0.15%, hydroxypropyl-β-cyclodextrin 0.3%, purified water balance; In the sodium hyaluronate, the mass ratio of low molecular weight sodium hyaluronate (100,000~800,000), medium molecular weight sodium hyaluronate (800,000~1,300,000), and high molecular weight sodium hyaluronate (1,800,000~2,200,000) is 1:0.6:0.3, and all are manufactured by Xi'an Zebang Biotechnology Co., Ltd. The manufacturer of trehalose is Zhengzhou Longsheng Chemical Products Co., Ltd. The manufacturer of polyglutamic acid (cosmetic grade) is Xi'an Aosai Biotechnology Co., Ltd. The manufacturer of rosmarinic acid is Chengdu Purifa Technology Development Co., Ltd. The manufacturer of Vitamin B12 is Shanghai Yuanye Biotechnology Co., Ltd. The manufacturer of the boric acid-borax buffer solution is Wujiang Xinli Fine Chemical Co., Ltd. The sodium chloride is manufactured by Henan Guangheng Food Ingredients Co., Ltd. The manufacturer of potassium sorbate is Xi'an Xinfengda Pharmaceutical Excipients Co., Ltd. The manufacturer of hydroxypropyl-β-cyclodextrin is Shandong Binzhou Zhiyuan Biotechnology Co., Ltd.

[0099] This embodiment also provides a method for preparing a lubricating eye drop specifically for silicone hydrogel contact lenses to relieve dry eye syndrome, including the following steps: Add 70% of the total amount of water for injection (45℃) to the preparation tank, then add boric acid-borax buffer, sodium chloride, and potassium sorbate in sequence, stir until completely dissolved (60 min), and cool to 30℃ to obtain the first mixture; In another container, hydroxypropyl-β-cyclodextrin and rosmarinic acid were added to 10% water for injection and homogenized (10,000 rpm, 5 min) to form an inclusion complex, thus obtaining a second mixture. The taurine-hyaluronic acid conjugate was dispersed in 5% water for injection to obtain a third mixture; Vitamin B12 was pre-dissolved in 0.5% warm water for injection to obtain the fourth mixture; Add the lubricant to 8% water for injection to obtain the fifth mixture; Add the second mixture to the end of the first mixture and stir gently for 15 minutes. Maintain the temperature at 30°C and slowly add the sodium hyaluronate mixture, polyglutamic acid, and trehalose in sequence, stirring at low speed (200 rpm) for 2 hours to ensure complete hydration. Add the third and fourth mixtures, maintain the temperature at 30°C, and stir for 40 minutes under light-protected conditions. Slowly inject the fifth mixture into the main preparation tank, avoiding high-speed shear (stirring speed 120 rpm), and adjust the pH to 7.4. Vacuum degas the mixture (-0.08 MPa, 20 minutes), add water for injection to the total volume, and pass through a 0.22 μm PES membrane to obtain a silicone hydrogel contact lens lubricating solution.

[0100] Example 2

[0101] This embodiment provides a silicone hydrogel contact lens eye drops for relieving dry eye syndrome, comprising the following components by mass fraction: Sodium hyaluronate 0.6%, trehalose 1.8%, polyglutamic acid 0.15%, lubricant 0.5% (hydroxyethyl cellulose-polyvinyl alcohol graft copolymer 0.4%, polydimethylsiloxane-polyether copolymer 0.1%), taurine-hyaluronic acid coupling agent 0.25%, rosmarinic acid 0.025%, vitamin B12 0.0015%, boric acid-borax buffer 0.25%, sodium chloride 0.7%, potassium sorbate 0.12%, hydroxypropyl-β-cyclodextrin 0.4%, purified water balance, and other parameters and conditions are the same as in Example 1.

[0102] Example 3

[0103] This embodiment provides a silicone hydrogel contact lens eye drops for relieving dry eye syndrome, comprising the following components by mass fraction: Sodium hyaluronate 0.3%, trehalose 1.0%, polyglutamic acid 0.25%, lubricant 0.9% (hydroxyethyl cellulose-polyvinyl alcohol graft copolymer 0.75%, polydimethylsiloxane-polyether copolymer 0.15%), taurine-hyaluronic acid coupling agent 0.1%, rosmarinic acid 0.015%, vitamin B12 0.0008%, boric acid-borax buffer 0.15%, sodium chloride 0.9%, potassium sorbate 0.18%, hydroxypropyl-β-cyclodextrin 0.2%, purified water balance, and other parameters and conditions are the same as in Example 1.

[0104] Comparative Example 1

[0105] The difference between Comparative Example 1 and Example 1 is that the polydimethylsiloxane-polyether copolymer was removed, while the other parameters and conditions were the same as in Example 1.

[0106] Comparative Example 2

[0107] The difference between Comparative Example 2 and Example 1 is that sodium hyaluronate was modified to include only medium molecular weight sodium hyaluronate, while other parameters and conditions were the same as in Example 1.

[0108] Comparative Example 3

[0109] The difference between Comparative Example 3 and Example 1 is that the taurine-hyaluronic acid conjugate was removed, while other parameters and conditions were the same as in Example 1.

[0110] The products obtained in Examples 1-3 and Comparative Examples 1-3 were subjected to the following performance tests, and the results are shown in Table 1: (1) Tear film breakup time (BUT): Simulates tear film stability (≥10s is acceptable); (2) Lens surface contact angle: to assess lens wettability; (3) Corneal fluorescein staining score (NEI standard): assesses ocular surface damage (0~15 points); (4) Subjective comfort score: score after wearing silicone hydrogel lenses (0~10 points); (5) Lens deposit rating: the degree of lens deposits after 7 days of wear (0~4).

[0111] Table 1. Performance test results of Examples 1-3 and Comparative Examples 1-3

[0112] As shown in Table 1, Examples 1-3 significantly outperformed the comparative examples due to the synergistic moisturizing effect of triple molecular weight sodium hyaluronate (70% increase in BUT), the efficient wetting of the lens hydrophobic interface by the silicone ether copolymer (42% reduction in contact angle), and the anti-inflammatory and repairing effect of the taurine conjugate (68% reduction in corneal damage). Comparative Example 1 suffered from deteriorated lens wettability (a sharp increase in contact angle of 71%) and collapsed tear film stability (BUT of only 8.3s) due to the lack of silicone ether copolymer; Comparative Example 2 experienced a 26% reduction in BUT due to the water-locking deficiency of single molecular weight HA; and Comparative Example 3 lacked taurine conjugate, resulting in weakened corneal repair ability (142% increase in damage score). Therefore, the eye drops obtained in this invention effectively alleviate dry eye symptoms in silicone hydrogel wearing scenarios.

[0113] Therefore, the eye drops of this invention significantly improve the relief of dry eye symptoms for silicone hydrogel wearers through the synergistic moisturizing effect of triple molecular weight HA, the improvement of lens hydrophobicity by a customized lubricant, and the anti-inflammatory and repairing effect of taurine conjugates. Example data confirm that it comprehensively improves tear film stability, ocular surface protection, and lens compatibility, making it particularly suitable for patients with moderate to severe dry eye syndrome.

[0114] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A lubricating eye drop specifically for silicone hydrogel contact lenses to relieve dry eye syndrome, characterized in that, Components containing the following mass fractions: Sodium hyaluronate 0.2-0.8%, trehalose 0.8-2.0%, polyglutamic acid 0.1-0.3%, lubricant 0.3-1.05%, taurine-hyaluronic acid coupling agent 0.08-0.3%, rosmarinic acid 0.01-0.03%, vitamin B12 0.0005-0.002%, buffer 0.1-0.3%, osmotic pressure regulator 0.5-1.0%, preservative 0.1-0.2%, solubilizer 0.1-0.5%, balance being water.

2. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The sodium hyaluronate includes a mixture of low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate and high molecular weight sodium hyaluronate; The low molecular weight sodium hyaluronate has a molecular weight of 100,000 to 800,000; the medium molecular weight sodium hyaluronate has a molecular weight of 800,000 to 1,300,000; and the high molecular weight sodium hyaluronate has a molecular weight of 1,800,000 to 2,200,000. The mass ratio of the low molecular weight sodium hyaluronate, the medium molecular weight sodium hyaluronate, and the high molecular weight sodium hyaluronate is 1:0.5~0.7:0.2~0.

4.

3. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The lubricant comprises hydroxyethyl cellulose-polyvinyl alcohol graft copolymer and polydimethylsiloxane-polyether copolymer; the mass fraction of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer in the eye drops is 0.25~0.9%; the mass fraction of the polydimethylsiloxane-polyether copolymer in the eye drops is 0.05~0.15%.

4. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 3, characterized in that, The preparation method of the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer includes the following steps: under a protective atmosphere, hydroxyethyl cellulose, polyvinyl alcohol, initiator and water are mixed, the pH is adjusted to 5.5~6.5, and a copolymerization reaction is carried out; after the reaction is completed, a terminator is added to obtain the hydroxyethyl cellulose-polyvinyl alcohol graft copolymer. The mass ratio of hydroxyethyl cellulose to polyvinyl alcohol is 1~3:1; the mass of the initiator is 0.5~1.5% of the total mass of hydroxyethyl cellulose and polyvinyl alcohol; the conditions for the copolymerization reaction include: temperature of 65~80℃ and time of 2~4h. The preparation method of the polydimethylsiloxane-polyether copolymer includes the following steps: under a protective atmosphere, hydrogen-terminated polydimethylsiloxane, allyl polyethylene glycol, inhibitor, catalyst and toluene are mixed and an addition reaction is carried out to obtain polydimethylsiloxane-polyether copolymer; The mass ratio of the hydrogen-terminated polydimethylsiloxane to the allyl polyethylene glycol is 1:0.7~1.0; the catalyst is a cassiterite catalyst; based on the mass of Pt in the catalyst, the amount of the catalyst is 0.01~0.05% of the total mass of the hydrogen-terminated polydimethylsiloxane and the allyl polyethylene glycol; the conditions for the addition reaction include: a temperature of 70~85℃ and a time of 3~5h.

5. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The preparation method of the taurine-hyaluronic acid coupling compound includes the following steps: under a protective atmosphere, activated taurine, sodium hyaluronate and water are mixed to carry out a coupling reaction, dialyzed and freeze-dried to obtain the taurine-hyaluronic acid coupling compound. The molar ratio of taurine to sodium hyaluronate used in the activated taurine is 6-9:1; the conditions for the coupling reaction include: pH 5-6, temperature 30-45℃, and time 18-30h.

6. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The buffer is a boric acid-borax buffer solution.

7. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The osmotic pressure regulator is sodium chloride.

8. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The preservative is potassium sorbate.

9. The silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to claim 1, characterized in that, The solubilizer is hydroxypropyl-β-cyclodextrin.

10. A method for preparing a silicone hydrogel contact lens lubricating solution for relieving dry eye syndrome according to any one of claims 1 to 9, characterized in that, Includes the following steps: Mix 70% of the total mass of water, buffer, osmotic pressure regulator and preservative to obtain the first mixture; Mix and homogenize 10% of the total mass of water, solubilizer, and rosmarinic acid to obtain a second mixture; A third mixture was obtained by mixing 5% of the total mass of water with the taurine-hyaluronic acid coupling agent. Mix 0.5% of the total mass of water with vitamin B12 to obtain the fourth mixture; Mix 8% of the total mass of water with lubricant to obtain the fifth mixture; The first and second mixtures are combined, and sodium hyaluronate, polyglutamic acid, and trehalose are added and mixed. Then, the third, fourth, and fifth mixtures are added and mixed with the remaining water to obtain a silicone hydrogel contact lens lubricating solution.

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