An ophthalmic composition for alleviating dry eye and asthenopia, and a preparation method and use thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an eye composition for relieving dry eye and visual fatigue, and a preparation method and application thereof. The application constructs a five-in-one whole-pathway intervention system for dry eye and visual fatigue, i.e. "controlling evaporation-supplementing water-dividing palpebral fissure-repairing cornea-reducing fatigue", and each raw material synergistically acts to realize comprehensive improvement which cannot be achieved by single-acting preparations. The synergistic effect is not a simple superposition of the effects of each component, but a precise intervention and functional complementation based on multiple pathological pathways of dry eye and visual fatigue, which fully embodies the creativity and unpredictable technical effects of the application in the design of the formula.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an ophthalmic composition for relieving dry eyes and visual fatigue, its preparation method, and its application. Background Technology

[0002] Currently, commercially available products for relieving dry eyes and eye fatigue have the following shortcomings: Ordinary artificial tears mostly contain only sodium hyaluronate, a single molecular weight substance, which can temporarily replenish the aqueous layer but cannot rebuild the lipid barrier of the outermost layer of the tear film, leading to rapid water evaporation, short-lasting moisturizing effect, and the need for frequent use; oil-containing products, due to poor compatibility between lipids and tears, easily cause blurred vision. Regarding eye fatigue relief, mainstream cooling eye drops often rely on vasoconstrictors, which, while providing an immediate cooling sensation, easily cause rebound congestion and increased fatigue after the medication takes effect, and lack substantial improvement on periocular microcirculation and ciliary muscle spasm. Furthermore, existing products have limited functions; moisturizing, anti-fatigue, corneal repair, and eyelid margin cleaning effects are isolated, and there is no technical solution that organically integrates multiple mechanisms of action into a single composition; corneal repair preparations often use costly and unstable protein components, while eyelid margin cleaning products suffer from strong irritation or insufficient cleaning efficacy.

[0003] Therefore, there is an urgent need to develop a comprehensive eye care composition that can synergistically achieve tear film stabilization, eye fatigue relief, corneal repair, and source cleaning. Summary of the Invention

[0004] The purpose of this invention is to provide an ophthalmic composition for relieving dry eyes and eye fatigue, as well as its preparation method and application.

[0005] To achieve the above objectives, the present invention provides the following technical solution: This invention provides an ophthalmic composition for relieving dry eyes and visual fatigue, comprising, by weight percentage: 0.01-1.0% terbufoto, 0.1-0.3% cooling agent, 0.01-0.05% soybean lecithin, 0.01-0.1% full-spectrum sodium hyaluronate, 0.01-0.1% polynucleotide, 0.0001-0.01% lutein, 0.01-0.8% tromethamine, 0.1-2.0% tromethamine hydrochloride, 0.05-1% mannitol, 0.1-0.5% sorbitol, 0-0.01% benzoyl chloride, and the balance being water.

[0006] Preferably, the cooling agent comprises, by weight percentage, 2-3% borneol, 0.5-1% menthol, 25-35% propylene glycol, 25-35% hydroxypropyl-β-cyclodextrin, and the balance being water.

[0007] Preferably, the full-spectrum sodium hyaluronate includes low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate; The mass ratio of the low molecular weight sodium hyaluronate, the medium molecular weight sodium hyaluronate, and the high molecular weight sodium hyaluronate is (1~3):(2~4):(4~6); The low molecular weight sodium hyaluronate has a molecular weight <1000 Da, the medium molecular weight sodium hyaluronate has a molecular weight of 10,000 to 500,000 Da, and the high molecular weight sodium hyaluronate has a molecular weight >1,000,000 Da. The molecular weight of the polynucleotide is 500~3000 Da.

[0008] Preferably, the pH value of the ophthalmic composition is 6.0 to 8.0, and the osmotic pressure is 150 to 280 mOsm / kg.

[0009] The present invention also provides a method for preparing the ophthalmic composition for relieving dry eyes and visual fatigue as described in the above technical solution, comprising the following steps: Step 1: Mix some water and full-spectrum sodium hyaluronate to obtain the first mixture; Step 2: Mix the first mixture, tylosap, and soybean lecithin to obtain the second mixture; Step 3: Mix the second mixture, tromethorphan, tromethorphan hydrochloride, sorbitol, mannitol, lutein, and benzoyl chloride to obtain the third mixture; Step 4: Cool the third mixture to no more than 15°C, add polynucleotides and a cooling agent, and add water to bring the volume to 100%. Then, homogenize and mature the mixture to obtain the ophthalmic composition.

[0010] Preferably, in step 1, the mixing temperature is 20~25℃, the mixing is carried out under stirring conditions, the stirring speed is 60~120rpm, and the time is 120~150min.

[0011] Preferably, in step 2, the mixing includes: adding tylosap to the first mixture and stirring to dissolve it, obtaining a dissolved system; pre-dispersing soybean lecithin in water, homogenizing it, and then adding it to the dissolved system, followed by stirring and dispersing; the stirring speed for dissolving is 100~300 rpm, and the time is 20~40 min; the ratio of soybean lecithin to water is 1:3~7; the homogenization speed is 1000~10000 rpm, and the time is 3~10 min; the stirring speed for dispersing is 30~90 rpm, and the time is 30~60 min.

[0012] Preferably, in step 3, the mixing includes: adding tromethorphan, tromethorphan hydrochloride, sorbitol, and mannitol to the second mixture, stirring to dissolve, and then adding lutein and benzoyl chloride; After mixing, the pH of the system is adjusted to 6.8±0.3, and the osmotic pressure of the system is adjusted to 290±15mOsm / kg.

[0013] Preferably, in step 4, the temperature of the third mixture is 10~15℃; The mixing process includes: dissolving the polynucleotide in water, adding it to a cooled third mixture, and stirring to disperse it; then adding a cooling agent and stirring to combine it; the mass ratio of the polynucleotide to water is 1:3~7; the stirring speed is 30~70 rpm and the time is 10~30 min; the stirring time is 3~5 h. The preparation of the cooling agent includes: dissolving hydroxypropyl-β-cyclodextrin in water to obtain a cyclodextrin solution; grinding and melting menthol and borneol together, dissolving them in propylene glycol, and then adding them to the cyclodextrin solution to obtain the cooling agent; After adding water to bring the volume to 100%, the process also includes stirring, with the stirring speed being 30~90 rpm and the time being 10~30 min; The homogenization speed is 1000~5000 rpm, and the time is 5~15 min; The maturation process is a closed, room-temperature, static maturation process, and the maturation time is 6 to 15 hours.

[0014] The present invention also provides the application of the ophthalmic composition described in the above technical solution or the ophthalmic composition prepared by the preparation method described in the above technical solution in the preparation of a medicine for relieving dry eyes and visual fatigue.

[0015] Compared with the prior art, the beneficial effects of the present invention include: This invention innovatively employs a transdermal drug delivery technology route through acupoints around the eyes. Through the optimized combination of menthol and borneol, it synergistically promotes the gentle promotion of microcirculation in the subcutaneous capillaries around the eyes and effectively relieves ciliary muscle spasm, blocking the occurrence of eye fatigue from the core pathological link. At the same time, the soy lecithin and full-spectrum sodium hyaluronate in the formula can stabilize the tear film structure for a long time and specifically eliminate secondary fatigue of dry eyes caused by excessive tear film breakup. Meanwhile, polynucleotides synergistically with sodium hyaluronate can repair microscopic damage to the corneal epithelium accumulated from long-term eye use and eliminate conductive fatigue induced by foreign body sensation and stinging. This invention improves eye fatigue through multiple synergistic pathways. Compared to traditional cooling eye drops that are directly instilled into the conjunctival sac, it completely eliminates vasoconstrictors such as naphazoline, thus fundamentally avoiding rebound congestion and irritation after medication. Furthermore, its transdermal absorption pathway achieves significant advantages such as zero conjunctival irritation, rapid onset of action, and long-lasting effect. A series of experimental data have fully verified its superior comprehensive efficacy in combating eye fatigue. In addition, teroxaprol is a non-ionic, mild surfactant with a hydrophilic-lipophilic balance suitable for the periorbital area. It emulsifies and dissolves eyelid margin oil plugs, dust, and cosmetic residues without damaging the meibomian gland's native oil or the ocular surface mucosa, thus addressing the root cause of dry eye induced by eyelid margin blockage.

[0016] This invention constructs a five-in-one comprehensive intervention system for dry eye and visual fatigue, encompassing "evaporation control, hydration replenishment, tarsal plate unblocking, corneal repair, and fatigue relief." The synergistic effects of each ingredient achieve a comprehensive improvement that is difficult to achieve with single-function formulations. Clinical trials involving 30 participants for 28 consecutive days have verified that, compared to single-function eye care formulations on the market, this product shows improvements exceeding 65% in three core indicators: tear film stability (prolonged tear film exposure), corneal repair (reduction in corneal fluorescein staining score), and fatigue relief (reduction in VAS score), with statistically significant differences. This synergistic effect is not a simple additive of the individual component's efficacy, but rather a precise intervention and functional complementarity based on multiple pathological pathways of dry eye and visual fatigue, fully demonstrating the creativity in the formulation design and the unpredictable technical effects of this invention.

[0017] This invention ensures that tylosap, lecithin, full-spectrum HA, polynucleotides, and cooling components each perform their respective functions and work synergistically by limiting the grade of each raw material, precise proportioning, and stepwise temperature control. The preparation conditions are mild, the heat-sensitive active substances are completely preserved, the finished product has good stability, and its properties and efficacy indicators show no significant changes after 6 months of high-temperature sealed storage. Detailed Implementation

[0018] This invention provides an ophthalmic composition for relieving dry eyes and visual fatigue, comprising, by weight percentage: 0.01-1.0% terbufotazone, 0.1-0.3% cooling agent, 0.01-0.05% soybean lecithin, 0.01-0.1% full-spectrum sodium hyaluronate, 0.01-0.1% polynucleotide, 0.0001-0.01% lutein, 0.01-0.8% tromethamine, 0.1-2.0% tromethamine hydrochloride, 0.05-1% mannitol, 0.1-0.5% sorbitol, 0.000-0.01% benzoyl chloride, and the balance being water.

[0019] The ophthalmic composition provided by this invention comprises 0.01-1.0% teroxaprol by weight, specifically 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1.0%. In this method, the teroxaprol is preferably medical grade. As a nonionic surfactant, teroxaprol is cleansing without irritation, achieving emulsification and cleaning of eyelid margin oils, and forming a solubilizing system.

[0020] The ophthalmic composition provided by this invention comprises 0.1-0.3% cooling agent by weight percentage, specifically 0.1%, 0.2%, or 0.3%. In this invention, the cooling agent preferably comprises 2-3% borneol, 0.5-1% menthol, 25-35% propylene glycol, 25-35% hydroxypropyl-β-cyclodextrin, and the balance water by weight percentage; more preferably, it comprises 2.42% borneol, 0.81% menthol, 32.26% propylene glycol, 32.26% hydroxypropyl-β-cyclodextrin, and the balance water. In this invention, the cooling agent can stimulate acupoints, relieve eye fatigue, and dilate microcirculation.

[0021] The ophthalmic composition provided by this invention comprises 0.01-0.05% soybean lecithin by weight percentage, specifically 0.01%, 0.02%, 0.03%, 0.04%, and 0.05%. In this invention, the soybean lecithin is refined pharmaceutical-grade lecithin, which can moisturize the ocular surface, reduce friction, and alleviate discomfort; replenish the tear lipid layer, reduce tear evaporation, stabilize the tear film, and prolong breakup time; the human natural tear film consists of a lipid layer (outermost layer), an aqueous layer (middle layer), and a mucin layer (inner layer). Dry eyes are mostly caused by meibomian gland abnormalities and lipid layer defects, leading to rapid water evaporation. The structure of soybean lecithin is homologous to the lipids secreted by human meibomian glands. After being sprayed onto the ocular surface, it spreads evenly to form a continuous biomimetic lipid film, blocking tear evaporation channels and reducing water loss from the source.

[0022] The ophthalmic composition provided by this invention comprises 0.01-0.1% full-spectrum sodium hyaluronate by weight percentage, specifically 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.1%. In this invention, the full-spectrum sodium hyaluronate preferably comprises low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate; the preferred mass ratio of the low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate is (1-3):(2-4):(4-6), specifically 2:3:5; the molecular weight of the low molecular weight sodium hyaluronate is preferably <1000 Da, the molecular weight of the medium molecular weight sodium hyaluronate is preferably 10,000-500,000 Da, and the molecular weight of the high molecular weight sodium hyaluronate is preferably >1,000,000 Da. In this invention, the full-spectrum sodium hyaluronate is preferably medical device grade, with molecular weights ranging from low to high. It replenishes the aqueous layer in layers: a high-molecular-weight surface layer locks in moisture, a medium-molecular-weight layer fills the aqueous layer, and a low-molecular-weight layer penetrates the epithelium to replenish moisture. Specifically: high-molecular-weight HA remains on the surface of the tear film, forming a highly hydrated gel film that physically locks in moisture and reduces moisture loss from the surrounding air; medium-molecular-weight HA fills the tear film gaps, increasing the aqueous layer capacity; and low-molecular-weight HA penetrates the corneal epithelial gaps, enters the interstitial space, replenishes intracellular moisture, and improves cellular dehydration. In this invention, lecithin and full-spectrum sodium hyaluronate are combined: lecithin controls evaporation, and full-spectrum HA provides double-layer hydration, completely reconstructing the artificial physiological tear film.

[0023] The ophthalmic composition provided by this invention comprises 0.01-0.1% polynucleotide by weight, specifically 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%. In this invention, the molecular weight of the polynucleotide is preferably 500-3000 Da. In this invention, the polynucleotide is preferably medical device grade, derived from salmon, and belongs to small molecule nucleic acid fragments. It can serve as a nutrient substrate for corneal epithelial cells, promoting corneal epithelial cell proliferation and accelerating wound healing; simultaneously, it inhibits the release of ocular surface inflammatory factors IL-6 and TNF-α, improving mild allergic and frictional ocular surface inflammation, and synergistically accelerates creeping wound healing with sodium hyaluronate. Simultaneously, polynucleotides promote collagen synthesis in the dermis around the eyes, thickening the dermis and improving dark circles caused by vascular permeability; low-molecular-weight HA deeply hydrates and improves dryness and dullness around the eyes; combined with massage, it promotes skin absorption and enhances the transdermal absorption rate of active ingredients.

[0024] The ophthalmic composition provided by the present invention comprises 0.0001% to 0.01% lutein by weight, specifically 0.0001%, 0.0005%, 0.001%, 0.005%, or 0.01%. In the present invention, the lutein can improve retinal microcirculation, increase blood flow, and enhance visual acuity and contrast sensitivity.

[0025] The ophthalmic composition provided by the present invention comprises 0.01-0.8% tromethamine by weight, specifically 0.01%, 0.05%, 0.1%, 0.18%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, and 0.8%. In the present invention, the tromethamine is preferably pharmaceutical grade.

[0026] The ophthalmic composition provided by this invention comprises 0.1-2.0% tromethamine hydrochloride by weight, specifically 0.1%, 0.5%, 1.0%, 1.2%, 1.3%, 1.5%, and 2.0%. In this invention, the tromethamine hydrochloride is preferably pharmaceutical grade. In this invention, the tromethamine and tromethamine hydrochloride serve as acid-base buffers.

[0027] The ophthalmic composition provided by the present invention comprises 0.05-1% mannitol by weight, specifically 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%. In the present invention, the mannitol is preferably pharmaceutical grade.

[0028] The ophthalmic composition provided by this invention comprises 0.1-0.5% sorbitol by weight percentage, specifically 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%. In this invention, the sorbitol is preferably pharmaceutical grade. In this invention, the mannitol and sorbitol are preferably osmotic pressure regulators.

[0029] The ophthalmic composition provided by this invention comprises 0-0.01% benzodiazepine chloride by weight percentage, specifically 0, 0.001%, 0.005%, or 0.01%. In this invention, the benzodiazepine chloride is preferably pharmaceutical grade. In this invention, the benzodiazepine chloride is preferably a preservative.

[0030] In this invention, the water is preferably water for injection.

[0031] In this invention, the pH value of the ophthalmic composition is preferably 6.0 to 8.0, and the osmotic pressure is preferably 150 to 280 mOsm / kg, specifically 150 mOsm / kg, 180 mOsm / kg, 200 mOsm / kg, 220 mOsm / kg, 250 mOsm / kg, and 280 mOsm / kg.

[0032] The mechanism of action of the ophthalmic composition provided by this invention is as follows: (1) Improve microcirculation and rapidly metabolize fatigue-causing factors: The core ingredients menthol and borneol penetrate through the skin around the eyes and acupoints above and below the orbit, with very little direct contact with the eyeball. The two work together to gently dilate the subcutaneous capillaries around the eyes, accelerate local blood circulation in the eyes, and quickly remove lactic acid and fatigue-causing inflammatory metabolites that accumulate due to excessive eye use, effectively relieving discomfort such as eye soreness and tightness.

[0033] (2) Blocking the core cause of fatigue and relaxing the accommodative muscles: Persistent ciliary muscle spasm caused by prolonged close-range use of the eyes is the core pathological basis for blurred vision, dryness and fatigue. Peppermint and borneol can act on the superficial nerve endings around the eyes, soothe the spasmed ciliary muscles through the nerve reflex pathway, relax the overall accommodative muscles of the eyes, and fundamentally improve the state of visual fatigue from a physiological level.

[0034] (3) Safety advantages: Zero irritation, no rebound. This product is mainly for external use, effectively avoiding the transient conjunctival congestion, brief stinging and other irritating reactions caused by direct instillation of traditional eye drops into the conjunctival sac. The formula does not contain vasoconstrictors such as naphazoline, and long-term use will not cause rebound congestion or increased fatigue after discontinuation, making it safer.

[0035] (4) Synergistic and auxiliary effects: addressing both the symptoms and the root cause. Stabilizing the tear film (treating the symptoms): The combination of soybean lecithin and full-spectrum sodium hyaluronate can stabilize the tear film structure of the ocular surface for a long time, compensate for dry eye fatigue caused by excessive tear film breakup, and reduce compensatory frequent blinking caused by dryness of the ocular surface. Repairing micro-damage (strengthening the root cause): The addition of polynucleotides can target and repair micro-damage to the corneal epithelium caused by long-term use of the eyes, eliminate secondary eye fatigue induced by corneal foreign body sensation and stinging, and achieve a synergistic anti-fatigue effect of "immediate relief + long-term repair".

[0036] (5) Tylosap is a non-ionic, mild surfactant with a hydrophilic-lipophilic balance suitable for the eye area. It emulsifies and dissolves eyelid oil plugs, dust, and cosmetic residues without damaging the meibomian glands' natural oils or the ocular surface mucosa, thus solving the root cause of dry eye caused by eyelid blockage.

[0037] The steps for using the ophthalmic composition provided by the present invention can be performed sequentially or individually as follows: (1) spraying and wiping clean with eyes closed; (2) spraying with eyes open; (3) combined with periocular massage.

[0038] The present invention also provides a method for preparing the ophthalmic composition described above, comprising the following steps: Step 1: Mix some water and full-spectrum sodium hyaluronate to obtain the first mixture; Step 2: Mix the first mixture, tylosap, and soybean lecithin to obtain the second mixture; Step 3: Mix the second mixture, tromethorphan, tromethorphan hydrochloride, sorbitol, mannitol, lutein, and benzoyl chloride to obtain the third mixture; Step 4: Cool the third mixture to no more than 15°C, add polynucleotides and a cooling agent, and add water to bring the volume to 100%. Then, homogenize and mature the mixture to obtain the ophthalmic composition.

[0039] Step 1 of the present invention involves mixing a portion of water and full-spectrum sodium hyaluronate to obtain a first mixture.

[0040] In this invention, the portion of water preferably accounts for 70% of the total water consumption.

[0041] In this invention, in step 1, the mixing temperature is preferably 20~25℃, specifically 20℃, 21℃, 22℃, 23℃, 24℃, or 25℃; the mixing is preferably carried out under stirring conditions, the stirring speed is preferably 60~120 rpm, specifically 60 rpm, 70 rpm, 80 rpm, 90 rpm, 100 rpm, 110 rpm, or 120 rpm; the time is 120~150 min, specifically 120 min, 130 min, 140 min, or 150 min; the mixing process is preferably as follows: under stirring conditions, full-spectrum sodium hyaluronate is added to water in small amounts multiple times until the full-spectrum sodium hyaluronate is completely swollen, there are no visible particles, and the solution is homogeneous and transparent; sodium hyaluronate must not be added in large quantities at once to prevent clumping and insolubility.

[0042] After obtaining the first mixture, step 2 of the present invention is to mix the first mixture, tylosap, and soybean lecithin to obtain the second mixture.

[0043] In this invention, step 2, the mixing preferably includes: adding tylosap to the first mixture and stirring to dissolve it, obtaining a dissolved system; pre-dispersing soybean lecithin in water and homogenizing it, then adding it to the dissolved system and stirring to disperse it; the stirring speed is preferably 100~300 rpm, specifically 100 rpm, 120 rpm, 150 rpm, 200 rpm, 220 rpm, 250 rpm, or 300 rpm; the stirring time is preferably 20~40 min, specifically 20 min, 30 min, or 40 min; the ratio of soybean lecithin to water is preferably 1:3~7, specifically 1:3, 1:4, 1:5, 1:6, or 1:7; The preferred homogenization speed is 1000-10000 rpm, specifically 1000 rpm, 5000 rpm, 8000 rpm, or 10000 rpm; the preferred time is 3-10 min, specifically 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, or 10 min. The preferred stirring and dispersion speed is 30-90 rpm, specifically 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, or 90 rpm; the preferred time is 30-60 min, specifically 30 min, 40 min, 50 min, or 60 min, to achieve uniform lipid dispersion without stratification. In this invention, soybean lecithin must be pre-dispersed before feeding to avoid floating and stratification, and tylosap is added to form a homogeneous solution.

[0044] After obtaining the second mixture, step 3 of the present invention is to mix the second mixture, tromethorphan, tromethorphan hydrochloride, sorbitol, mannitol, lutein, and benzoyl chloride to obtain the third mixture.

[0045] In this invention, step 3, the mixing preferably includes: adding tromethamine, tromethamine hydrochloride, sorbitol, and mannitol to a second mixture, stirring to dissolve, and then adding lutein and benzoyl chloride; the stirring and dissolving time is preferably 30 minutes. In this invention, after mixing, it is also preferred to adjust the pH of the system to 6.8±0.3 and the osmotic pressure of the system to 290±15 mOsm / kg; the reagents used to adjust the pH of the system preferably include dilute hydrochloric acid and / or sodium hydroxide; the osmotic pressure is preferably detected using an osmometer, and the amount of sorbitol is finely adjusted to control the final osmotic pressure to 290±15 mOsm / kg, which conforms to the physiological osmotic pressure range of the human eye.

[0046] After obtaining the third mixture, step 4 of the present invention involves cooling the third mixture to no more than 15°C, adding polynucleotides and a cooling agent, and adding water to bring the volume to 100%. The mixture is then homogenized and matured sequentially to obtain the ophthalmic composition.

[0047] In this invention, in step 4, the temperature of the third mixture is preferably 10-15°C, specifically 10°C, 11°C, 12°C, 13°C, 14°C, or 15°C; the mixing preferably includes: dissolving the polynucleotide in water, adding it to the cooled third mixture, and stirring to disperse; then adding a cooling agent and stirring to combine; the mass ratio of the polynucleotide to water is 1:3-7, specifically 1:3, 1:4, 1:5, 1:6, or 1:7; the stirring speed is preferably 30-70 rpm, specifically 30 rpm, 40 rpm, 50 rpm, 60 rpm, or 70 rpm; the time is preferably 10-30 min, specifically 10 min, 20 min, or 30 min; the stirring time is 3-5 h, specifically 3 h, 4 h, or 5 h. In this invention, the preparation of the cooling agent preferably includes: dissolving hydroxypropyl-β-cyclodextrin in water to obtain a cyclodextrin solution; co-grinding and melting menthol and borneol, dissolving them in propylene glycol, and then adding the cyclodextrin solution to obtain the cooling agent. In this invention, borneol and menthol are first co-grinded and melted and then added to the hydroxypropyl-β-cyclodextrin solution to obtain the cooling agent. The addition of the cooling agent and the polynucleotide is carried out at low temperatures throughout the process to avoid high-temperature inactivation and volatilization.

[0048] In this invention, after adding water to a final volume of 100%, stirring is preferably performed. The stirring speed is preferably 30-90 rpm, specifically 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, or 90 rpm; the stirring time is preferably 10-30 min, specifically 10 min, 20 min, or 30 min. In this invention, the homogenization speed is preferably 1000-5000 rpm, specifically 1000 rpm, 2000 rpm, 3000 rpm, 4000 rpm, or 5000 rpm; the homogenization time is preferably 5-15 min, specifically 5 min, 8 min, 10 min, 12 min, or 15 min, to eliminate small colloidal particles. In this invention, the maturation is preferably performed in a sealed container at room temperature for a maturation time of 6-15 hours, specifically 6 hours, 8 hours, 10 hours, 12 hours, or 15 hours; during the maturation process, no stratification, precipitation, or turbidity is observed.

[0049] In this invention, after the curing process, it is preferable to further include filtration and finished product packaging; the filtration is preferably aseptic filtration, and more preferably a two-stage pressurized aseptic filtration using a 0.22μm aqueous microporous filter membrane; the finished product packaging is preferably quantitative filling into medical spray bottles under aseptic conditions and sealing to obtain the finished product.

[0050] The present invention also provides the application of the ophthalmic composition described in the above technical solution or the ophthalmic composition prepared by the preparation method described in the above technical solution in the preparation of a medicine for relieving dry eyes and visual fatigue.

[0051] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0052] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0053] Examples 1-3 The formulations of the ophthalmic compositions in Examples 1-3 are shown in Table 1. The cooling agents, by mass percentage, include 2.42% borneol, 0.81% menthol, 32.26% propylene glycol, 32.26% hydroxypropyl-β-cyclodextrin, and the balance being water. The molecular weight of low molecular weight HA is <1000 Da, the molecular weight of medium molecular weight HA is 10,000 to 500,000 Da, and the molecular weight of high molecular weight HA is >1,000,000 Da. Table 1. Formulations (%) of the ophthalmic compositions in Examples 1-3

[0054] Preparation method: Step 1: Preparation of base solution At room temperature (25℃), weigh 70% of the total amount of water for injection prescribed and add it to a clean mixing tank. Turn on low-speed stirring (60 rpm). Add small amounts of the full-spectrum compound sodium hyaluronate powder (HA, low / medium / high in a ratio of 2:3:5 premixed evenly) to the water mixture and stir continuously at low speed for 120-150 minutes until the HA is completely swollen, there are no visible particles, and the solution is uniform and transparent to obtain the first mixture. Step 2: Feeding of surfactants and lipid components At room temperature of 25℃, tylosap was added to the first mixture in batches, and the stirring speed was increased to 120 rpm. The mixture was stirred for 30 minutes until completely dissolved. Soy lecithin was pre-dispersed with a small amount of water (material-to-liquid ratio 1:5), homogenized at 8000 rpm for 5 minutes using a high-speed homogenizer, and then slowly added to the mixing tank. The mixture was stirred at 60 rpm for 40 minutes to achieve uniform dispersion of lipids without stratification, thus obtaining the second mixture. Step 3: Buffer system preparation At room temperature (25℃), tromethorphan, tromethorphan hydrochloride, sorbitol, and mannitol were added to the second mixture and stirred for 30 minutes until completely dissolved. Lutein and benzoyl chloride were then added. The pH of the system was finely adjusted to 6.8±0.3 using a precision pH meter for real-time monitoring. The amount of sorbitol was finely adjusted using an osmometer to control the final osmotic pressure to 290±15 mOsm / kg, thus obtaining the third mixture. Step 4: Low-temperature feeding of thermosensitive active materials Cool the third mixture to 15°C, pre-dissolve the polynucleotide in 5 times the volume of low-temperature water for injection, and slowly and evenly add it to the container while stirring at 50 rpm for 20 minutes; grind menthol and borneol together into a molten liquid, then dissolve in propylene glycol; dissolve hydroxypropyl-β-cyclodextrin in water, then add the borneol and menthol solution to the cyclodextrin solution to obtain a cooling agent; slowly add the cooling agent dropwise to the container and stir for 4 hours. The above system was replenished with water for injection to 100% of the total weight, and the whole system was stirred at 60 rpm for 20 min. The system was then homogenized at a low speed of 3000 rpm for 8 min to eliminate small colloidal particles. The system was then allowed to stand at room temperature in a sealed environment for 12 h to mature, and no stratification, precipitation, or turbidity was observed. The eye spray is prepared by using a two-stage series pressurized aseptic filtration process with a 0.22μm aqueous microporous filter membrane, followed by quantitative filling into medical spray bottles under aseptic conditions and sealing.

[0055] Comparative Example 1 Commercially available single-molecule HA artificial tears; Formula: 0.16% medium molecular weight sodium hyaluronate (500,000 Da), 0.49% sodium chloride, 0.64% boric acid, 0.09% borax, and the balance water for injection.

[0056] Comparative Example 2 Traditional cooling eye drops available on the market; Formula: 0.1% naphazoline hydrochloride (vasoconstrictor) aqueous solution.

[0057] Performance testing Performance tests were conducted on the products of the embodiments and comparative examples; Among them, 30 people were tested for 28 consecutive days. All the testers were people with obvious dry eyes and eye fatigue, and they used it once a day. Clinically accepted indicators for diagnosing dry eye: (1) Tear film breakup time (BUT) is measured using the fluorescein staining method. A moistened strip of fluorescein filter paper is placed in the conjunctival sac of the subject. The subject blinks fully 3-4 times to distribute the fluorescein evenly on the corneal surface. The subject looks straight ahead and tries not to blink. A stopwatch is started, and the cornea is observed using a slit lamp equipped with a cobalt blue light filter. The time from the last blink to the appearance of the first dry spot on the cornea is recorded as the tear film breakup time (BUT).

[0058] (2) Visual Analogue Scale (VAS) for dry eyes: 0-10 points, the higher the score, the drier the eyes; Indicator definition: Assess the subject's subjective experience of dry eyes, 0 points = no dryness, 10 points = the most severe dry eyes that can be imagined; Test procedure: Tools: 100mm horizontal VAS ruler, left end 0 (no dryness), right end 10 (most severe dryness); the subject marks independently; measure the distance from 0 to the mark in millimeters ÷ 10 to obtain a score of 0-10.

[0059] (3) Visual fatigue subjective VAS score: 0-10 points, the higher the score, the more severe the fatigue; Indicator definition: Assess subjective feelings of eye fatigue such as eye strain, eye fatigue, and visual fatigue after using the eyes. 0 = no fatigue, 10 = extremely unbearable eye fatigue; Test procedure: Tools: 100mm VAS ruler, 0 points: no visual fatigue at all; 10 points: can imagine the most severe visual fatigue. Subjects mark independently; measure the distance from the 0 end to the mark in millimeters ÷ 10 to obtain a score of 0-10.

[0060] (4) The number of corneal staining spots. The fewer the positive spots, the less severe the damage. The maximum score is 15 spots. The corneal zonal counting method was used, with a total score of 0-15 points, and fluorescein staining was employed. Testing tools: Sodium fluorescein test paper, slit lamp microscope, cobalt blue light filter; Operating procedures: a. Dip a small amount of sterile saline solution into a sodium fluorescein test strip and gently touch the lower eyelid conjunctiva. Do not directly contact the cornea. b. Instruct the subject to blink 3-5 times to ensure the dye is evenly applied to the corneal surface; c. Adjust the slit lamp to cobalt blue light and the slit width to a moderate level, and divide the cornea into 5 quadrants: superior nasal, superior temporal, inferior nasal, inferior temporal, and central area; e. A maximum of 3 staining points are counted in each quadrant, and 5 quadrants × 3 points = a maximum of 15 points; punctate staining within each quadrant is counted, and staining that merges into a patch is accumulated as multiple points.

[0061] (5) Eyelid margin occlusion grade: Clinically, a 4-grade grading system for meibomian gland opening occlusion is commonly used, ranging from 0 to 3; the higher the grade, the more severe the eyelid margin occlusion. Tools: Slit-lamp microscope, used with slit-lamp photography for recording; Grading Standards: Grade 0: Meibomian gland openings are open, unobstructed, no sebaceous plugs on the eyelid margin, and clear sebum can be expelled by squeezing the eyelid margin. Grade 1: A few openings are blocked, and small sebaceous plugs can be seen in a few openings; most openings are unobstructed. Grade 2: Some openings are blocked, and sebaceous plugs and keratin plugs can be seen in multiple openings; some openings are raised, and cloudy oil can be seen by squeezing. Grade 3: A large number of openings are blocked, with extensive sebaceous plugs / keratin accumulation, raised eyelid margin openings, and most openings are closed; almost no sebum is expelled by squeezing. Test process: a. The subject is seated, and the upper and lower eyelid margins are observed with a slit lamp, with priority given to observing the meibomian gland openings; b. Fully expose the eyelid margin and observe whether there are keratin plugs, sebaceous plugs, bulging openings, or missing openings at the meibomian gland openings; Based on the above standards, a comprehensive congestion level is given.

[0062] The test results obtained from the above tests are shown in Table 2. Table 2 Performance test results of the examples and comparative products

[0063] The test results above show that: Example 1 has the best overall performance across all dimensions and is the preferred formula for industrial production. Example 2 causes no conjunctival irritation or redness, making it suitable for daily care for people who wear contact lenses. It is gentle and has the best safety profile. Example 3 has the fastest onset of action and is suitable for short-term intensive care for those who use their eyes intensively or suffer severe eye damage.

[0064] The artificial eye drops in Comparative Example 1 only provide temporary hydration and contain no lipids, repair, cleansing, or anti-fatigue components. The damaged cornea relies on its own self-healing, resulting in very low improvement in various aspects. In contrast to Comparative Example 1, this invention relies on a lecithin + full-spectrum HA + polynucleotide + cooling compound + tylosap compound system, which comprehensively and significantly outperforms existing products in five indicators: tear film stability, dry eye improvement, corneal repair, anti-fatigue, and eyelid margin cleansing. Comparative Example 2 relies on vasoconstriction for temporary relief, but fatigue rebound is obvious. It has no corneal repair or eyelid margin cleaning ability, is highly irritating, and is costly, unstable, and prone to deactivation. In contrast to Comparative Example 2, this invention has no irritating ingredients, no fatigue rebound problem, and significantly superior long-lasting anti-fatigue and corneal repair effects.

[0065] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An ophthalmic composition for relieving dry eyes and eye strain, characterized in that, The product comprises, by weight percentage: 0.01-1.0% tylosap, 0.1-0.3% cooling agent, 0.01-0.05% soy lecithin, 0.01-0.1% full-spectrum sodium hyaluronate, 0.01-0.1% polynucleotide, 0.0001-0.01% lutein, 0.01-0.8% tromethorphan, 0.1-2.0% tromethorphan hydrochloride, 0.05-1% mannitol, 0.1-0.5% sorbitol, 0-0.01% benzoyl chloride, and the balance being water.

2. The ophthalmic composition according to claim 1, characterized in that, The cooling agent comprises, by weight percentage, 2-3% borneol, 0.5-1% menthol, 25-35% propylene glycol, 25-35% hydroxypropyl-β-cyclodextrin, and the balance being water.

3. The ophthalmic composition according to claim 1, characterized in that, The full-spectrum sodium hyaluronate includes low molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate. The mass ratio of the low molecular weight sodium hyaluronate, the medium molecular weight sodium hyaluronate, and the high molecular weight sodium hyaluronate is (1~3):(2~4):(4~6); The low molecular weight sodium hyaluronate has a molecular weight <1000 Da, the medium molecular weight sodium hyaluronate has a molecular weight of 10,000 to 500,000 Da, and the high molecular weight sodium hyaluronate has a molecular weight >1,000,000 Da. The molecular weight of the polynucleotide is 500~3000 Da.

4. The ophthalmic composition according to claim 1, characterized in that, The ophthalmic composition has a pH value of 6.0 to 8.0 and an osmotic pressure of 150 to 280 mOsm / kg.

5. A method for preparing the ophthalmic composition for relieving dry eyes and visual fatigue according to any one of claims 1 to 4, characterized in that, Includes the following steps: Step 1: Mix some water and full-spectrum sodium hyaluronate to obtain the first mixture; Step 2: Mix the first mixture, tylosap, and soybean lecithin to obtain the second mixture; Step 3: Mix the second mixture, tromethorphan, tromethorphan hydrochloride, sorbitol, mannitol, lutein, and benzoyl chloride to obtain the third mixture; Step 4: Cool the third mixture to no more than 15°C, add polynucleotides and a cooling agent, and add water to bring the volume to 100%. Then, homogenize and mature the mixture to obtain the ophthalmic composition.

6. The preparation method according to claim 5, characterized in that, In step 1, the mixing temperature is 20~25℃, the mixing is carried out under stirring conditions, the stirring speed is 60~120rpm, and the time is 120~150min.

7. The preparation method according to claim 5, characterized in that, In step 2, the mixing includes: adding tylosap to the first mixture and stirring to dissolve it, thus obtaining a dissolved system; pre-dispersing soybean lecithin in water, homogenizing it, and then adding it to the dissolved system, followed by stirring to disperse it; the stirring speed for dissolving is 100-300 rpm, and the time is 20-40 min; the ratio of soybean lecithin to water is 1:3-7; the homogenization speed is 1000-10000 rpm, and the time is 3-10 min; the stirring speed for dispersion is 30-90 rpm, and the time is 30-60 min.

8. The preparation method according to claim 5, characterized in that, In step 3, the mixing includes: adding tromethamine, tromethamine hydrochloride, sorbitol, and mannitol to the second mixture, stirring to dissolve, and then adding lutein and benzoyl chloride. After mixing, the pH of the system is adjusted to 6.8±0.3, and the osmotic pressure of the system is adjusted to 290±15mOsm / kg.

9. The preparation method according to claim 5, characterized in that, In step 4, the temperature of the third mixture is 10~15℃; The mixing process includes: dissolving the polynucleotide in water, adding it to a cooled third mixture, and stirring to disperse it; then adding a cooling agent and stirring to combine it; the mass ratio of the polynucleotide to water is 1:3~7; the stirring speed is 30~70 rpm and the time is 10~30 min; the stirring time is 3~5 h. The preparation of the cooling agent includes: dissolving hydroxypropyl-β-cyclodextrin in water to obtain a cyclodextrin solution; grinding and melting menthol and borneol together, dissolving them in propylene glycol, and then adding them to the cyclodextrin solution to obtain the cooling agent; After adding water to bring the volume to 100%, the process also includes stirring, with the stirring speed being 30~90 rpm and the time being 10~30 min; The homogenization speed is 1000~5000 rpm, and the time is 5~15 min; The maturation process is a closed, room-temperature, static maturation process, and the maturation time is 6-15 hours.

10. The use of the ophthalmic composition according to any one of claims 1 to 4 or the ophthalmic composition prepared by the preparation method according to any one of claims 5 to 9 in the preparation of a medicament for relieving dry eyes and eye fatigue.

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