A contact lens based on composite drug microspheres and a preparation method and application thereof

Abstract

This invention provides a contact lens based on composite drug microspheres, its preparation method, and its application, belonging to the field of contact lens technology. The contact lens based on composite drug microspheres of this invention includes a lens matrix and composite drug core-shell microspheres dispersed in the lens matrix; the composite drug core-shell microspheres include a biodegradable polymer shell and a composite drug active ingredient encapsulated within the polymer shell; the composite drug active ingredient is cyclosporine A and sodium hyaluronate. This invention achieves high drug loading, long-term stable and controllable release, excellent lens compatibility, and superior in vivo therapeutic effects by constructing polydopamine-modified composite drug core-shell microspheres and stably integrating them into a silicone hydrogel matrix.

Description

Technical Field

[0001] This invention relates to the field of contact lens technology, and in particular to a contact lens based on composite drug microspheres, its preparation method, and its application. Background Technology

[0002] Dry eye syndrome, a common ocular surface disease, has become a significant health problem affecting patients' visual quality and quality of life. Current mainstream clinical treatments primarily rely on topical administration of artificial tears, anti-inflammatory drugs, and immunosuppressants. Cyclosporine A, a classic immunomodulator, effectively inhibits ocular surface inflammation; sodium hyaluronate, with its excellent moisturizing and lubricating properties, is a commonly used ingredient for relieving dry eyes. For example, Chinese invention patent application CN103191411A discloses a composition of cyclosporine A and an amphiphilic hyaluronic acid derivative, aiming to improve ocular bioavailability and reduce toxic side effects. However, this technology remains limited to traditional eye drops or in-situ gel formulations, failing to overcome the core bottleneck of short drug residence time on the ocular surface and the need for frequent administration.

[0003] To overcome the inherent limitations of traditional eye drops, prolong the duration of drug action, and improve patient compliance, drug-eluting contact lenses, a novel ocular drug delivery system, have attracted considerable attention and undergone in-depth research in recent years. Existing technologies are mainly divided into two categories: chemically bonded drug delivery technologies and physically blended drug delivery technologies, but both have significant limitations in their application.

[0004] Chemically bonded drug delivery technology typically achieves drug delivery by introducing functional groups into the lens polymer network that can undergo ion exchange or hydrogen bonding with the drug. For example, patent US9248928B2 discloses a method of packaging contact lenses containing carboxylic acid groups in a cationic drug solution, followed by sterilization to fix the drug to the lens through ion bonding. This method has three major drawbacks: first, the drug loading capacity is highly dependent on the ion content of the lens polymer, resulting in limited drug loading capacity and insufficient controllability; second, drug release is easily affected by tear ion strength, potentially leading to burst release and making it difficult to achieve stable and long-lasting release; and third, it is only suitable for ionic drugs that can undergo specific chemical interactions with the lens, and has poor compatibility with hydrophobic drugs such as cyclosporine A.

[0005] Physical blending drug delivery technology involves directly mixing the drug or its carrier into the lens molding material. Based on the carrier's morphology, it can be further subdivided into two types: 1) Direct blending method: As disclosed in Chinese invention patent CN103937025B, colloidal photonic crystal particles and anti-inflammatory agents are directly dispersed in a prepolymer and cured. Although this process is simple and easy to implement, the drug and matrix are loosely bound, the release rate is too fast, and the introduction of a large number of solid particles may damage the lens's light transmittance, mechanical strength, and wearing comfort.

[0006] 2) Nano / micro carrier blending method: This is a current research hotspot. Although it can achieve synergistic treatment and release monitoring and improve drug release behavior to a certain extent, it still faces three common challenges: First, the compatibility between the carrier and the hydrophilic lens matrix (such as hydrogel) is poor, and aggregation or sedimentation is prone to occur during the curing process, resulting in uneven lens and unbalanced drug distribution; Second, the carrier and matrix are only physically embedded, and the bonding force is weak. The carrier may be lost from the lens prematurely during wear, affecting the long-term treatment effect; Third, complex carrier structures (such as colored or special optical properties) may interfere with the normal visual function of the lens.

[0007] In summary, existing drug-eluting contact lens technologies, regardless of whether they employ chemical bonding or physical blending pathways, all have varying degrees of shortcomings in terms of controllable drug loading, long-term stable drug release, carrier-matrix stability, and wearing safety and comfort.

[0008] Therefore, it is of great significance to provide a contact lens that can achieve high drug loading, long-term stable and controllable release, and without affecting the basic optical and physical properties of the lens. Summary of the Invention

[0009] To address the aforementioned technical problems, the present invention aims to provide a contact lens based on composite drug microspheres, its preparation method, and its application.

[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a contact lens based on composite drug microspheres, the contact lens comprising a lens matrix and composite drug core-shell microspheres dispersed in the lens matrix; The composite drug core-shell microspheres include a biodegradable polymer shell and a composite drug active ingredient encapsulated within the polymer shell. The active ingredients of the compound drug are cyclosporine A and sodium hyaluronate.

[0011] Furthermore, the surface of the composite drug core-shell microspheres also includes a polydopamine modification layer.

[0012] Furthermore, the biodegradable polymer shell is a polylactic acid-glycolic acid copolymer; The lens matrix is ​​a silicone hydrogel.

[0013] This invention provides a method for preparing the aforementioned contact lens based on composite drug microspheres, comprising the following steps: 1) Dissolve sodium hyaluronate in water to obtain an inner aqueous phase; dissolve cyclosporine A and microsphere framework material in an organic solvent to obtain an oil phase; add the inner aqueous phase to the oil phase for primary emulsification to obtain a primary emulsion; 2) The primary emulsion and polyvinyl alcohol aqueous solution are emulsified twice to obtain a secondary emulsion. Finally, the secondary emulsion is solidified and centrifuged to obtain microspheres. 3) Disperse the microspheres in Tris-HCl buffer, add polydopamine to modify the surface of the microspheres, and obtain modified microspheres; 4) Mix the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer and photoinitiator to obtain a slurry; 5) The slurry is injected into the mold and cured by stepwise ultraviolet light under an inert atmosphere to obtain the lens blank; 6) The initial lens blank is solvent extracted in anhydrous ethanol, and then hydrated in phosphate buffer to obtain contact lenses.

[0014] Furthermore, the mass-to-volume ratio of sodium hyaluronate to water is 10-50 mg: 1 mL, and the molecular weight of sodium hyaluronate is 50-200 kDa; The microsphere framework material is a polylactic acid-glycolic acid copolymer, and the molecular weight of the microsphere framework material is 10,000 to 100,000. The organic solvent is dichloromethane and / or ethyl acetate; The ratio of cyclosporine A, microsphere framework material, and organic solvent is 5~30mg:100~500mg:3~10mL.

[0015] Furthermore, the mass ratio of sodium hyaluronate to cyclosporine A is 10~50:5~30; The primary emulsification speed is 10,000~15,000 rpm, and the primary emulsification time is 1~3 min.

[0016] Furthermore, the volume ratio of the primary emulsion to the polyvinyl alcohol aqueous solution is 1:20~50, and the mass fraction of the polyvinyl alcohol aqueous solution is 1~5%; The secondary emulsification speed is 6000~10000 rpm, and the secondary emulsification time is 2~5 min; The curing temperature is 20~40℃, the curing speed is 300~600rpm, and the curing time is 4~24h; The centrifugation speed is 3000~5000 rpm, and the centrifugation time is 5~15 min.

[0017] Furthermore, the ratio of the microspheres, Tris-HCl buffer, and polydopamine is 1 mg: 1 mL: 0.5~2.0 mg; The modification reaction is carried out at a temperature of 20-40°C, at a rotation speed of 50-200 rpm, and for a duration of 4-12 hours.

[0018] Furthermore, the crosslinking agent includes ethylene glycol dimethacrylate, the hydrophilic monomer includes N-vinylpyrrolidone, and the photoinitiator includes TPO; The mass ratio of the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer, and photoinitiator is 1~10:70~90:0.5~2:10~30:0.5~1.5; The stepped UV curing method is as follows: first, at 3~8mW / cm²... 2 Irradiate at an intensity of 30-50 seconds, followed by 12-18 mW / cm². 2 Irradiate at the intensity for 60-80 seconds; The solvent extraction temperature is 50~70℃, and the solvent extraction time is 2~6h; The hydration treatment temperature is 4~25℃, and the solvent extraction time is 12~48h.

[0019] The present invention also provides the application of the aforementioned composite drug microsphere-based contact lens in the preparation of a medical device for treating dry eye syndrome.

[0020] The beneficial effects of this invention are: 1) This invention encapsulates cyclosporine A and sodium hyaluronate together in the same core-shell microsphere, achieving synergistic anti-inflammatory and moisturizing effects while enabling programmed controlled release through a biodegradable polymer shell, thus avoiding the burst release problems of traditional eye drops' pulsed administration and physical blending techniques. 2) This invention improves the hydrophilicity and biocompatibility of composite drug core-shell microspheres by modifying the surface of the microspheres with polydopamine. Moreover, the abundant catechol groups can form strong hydrogen bonds, Michael additions or Schiff base reactions with the silica hydrogel matrix, thus fundamentally solving the technical problem of weak carrier-matrix bonding. This ensures that the microspheres are uniformly and stably dispersed in the lens and can be firmly anchored in the matrix network to prevent loss during use. 3) This invention uses core-shell microspheres as independent drug-carrying units. The drug loading and release kinetics can be independently controlled by the microsphere material and thickness, without being strictly limited by the lens matrix formulation. At the same time, the microspheres are uniformly embedded inside the lens, without affecting the smoothness of the lens surface, optical transparency, and the inherent high oxygen permeability and wearing comfort of the silicone hydrogel. 4) The preparation process of this invention is controllable. From the preparation of microspheres by the double emulsification method to the controllable modification of polydopamine, and then to the step-by-step ultraviolet curing molding, a complete and controllable process chain is formed, which has good repeatability and prospects for large-scale production. Detailed Implementation

[0021] This invention provides a contact lens based on composite drug microspheres, the contact lens comprising a lens matrix and composite drug core-shell microspheres dispersed in the lens matrix; The composite drug core-shell microspheres include a biodegradable polymer shell and a composite drug active ingredient encapsulated within the polymer shell. The active ingredients of the compound drug are cyclosporine A and sodium hyaluronate.

[0022] In this invention, the surface of the composite drug core-shell microspheres also includes a polydopamine modification layer.

[0023] In this invention, the biodegradable polymer shell is a polylactic acid-glycolic acid copolymer; The lens matrix is ​​a silicone hydrogel.

[0024] This invention provides a method for preparing the aforementioned contact lens based on composite drug microspheres, comprising the following steps: 1) Dissolve sodium hyaluronate in water to obtain an inner aqueous phase; dissolve cyclosporine A and microsphere framework material in an organic solvent to obtain an oil phase; add the inner aqueous phase to the oil phase for primary emulsification to obtain a primary emulsion; 2) The primary emulsion and polyvinyl alcohol aqueous solution are emulsified twice to obtain a secondary emulsion. Finally, the secondary emulsion is solidified and centrifuged to obtain microspheres. 3) Disperse the microspheres in Tris-HCl buffer, add polydopamine to modify the surface of the microspheres, and obtain modified microspheres; 4) Mix the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer and photoinitiator to obtain a slurry; 5) The slurry is injected into the mold and cured by stepwise ultraviolet light under an inert atmosphere to obtain the lens blank; 6) The initial lens blank is solvent extracted in anhydrous ethanol, and then hydrated in phosphate buffer to obtain contact lenses.

[0025] In this invention, the mass-to-volume ratio of sodium hyaluronate to water is 10-50 mg:1 mL, preferably 15-45 mg:1 mL, and more preferably 20-40 mg:1 mL; the molecular weight of sodium hyaluronate is 50-200 kDa, preferably 60-190 kDa, and more preferably 70-180 kDa. The microsphere framework material is a polylactic acid-glycolic acid copolymer, and the molecular weight of the microsphere framework material is 10,000 to 100,000, preferably 20,000 to 90,000, and more preferably 30,000 to 80,000. The organic solvent is dichloromethane and / or ethyl acetate, preferably dichloromethane; The ratio of cyclosporine A, microsphere framework material and organic solvent is 5~30mg:100~500mg:3~10mL, preferably 7~25mg:150~450mg:4~9mL, and more preferably 10~20mg:200~400mg:5~8mL.

[0026] In this invention, the mass ratio of sodium hyaluronate to cyclosporine A is 10~50:5~30, preferably 15~45:7~25, and more preferably 20~40:10~20; The primary emulsification speed is 10,000~15,000 rpm, preferably 11,000~14,000 rpm, and more preferably 12,000~13,000 rpm; the primary emulsification time is 1~3 min, preferably 1.5~2.5 min, and more preferably 2 min.

[0027] In this invention, the volume ratio of the primary emulsion to the polyvinyl alcohol aqueous solution is 1:20~50, preferably 1:25~45, more preferably 1:30~40; the mass fraction of the polyvinyl alcohol aqueous solution is 1~5%, preferably 1.5~4.5%, more preferably 2~4%; The rotation speed of the secondary emulsification is 6000~10000 rpm, preferably 7000~9000 rpm, and more preferably 8000 rpm; the secondary emulsification time is 2~5 min, preferably 2.5~4.5 min, and more preferably 3~4 min; The curing temperature is 20~40℃, preferably 25~35℃, and more preferably 30℃; the curing speed is 300~600rpm, preferably 350~550rpm, and more preferably 400~500rpm; the curing time is 4~24h, preferably 6~20h, and more preferably 8~16h. The centrifugation speed is 3000~5000rpm, preferably 3500~4500rpm, and more preferably 4000rpm; the centrifugation time is 5~15min, preferably 7~12min, and more preferably 10min.

[0028] In this invention, the ratio of microspheres, Tris-HCl buffer, and polydopamine is 1 mg: 1 mL: 0.5~2.0 mg, preferably 1 mg: 1 mL: 0.8~1.7 mg, and more preferably 1 mg: 1 mL: 1.0~1.5 mg; The temperature of the modification reaction is 20~40℃, preferably 25~35℃, and more preferably 30℃; the rotation speed of the modification reaction is 50~200rpm, preferably 70~180rpm, and more preferably 100~150rpm; the modification reaction time is 4~12h, preferably 6~10h, and more preferably 8h.

[0029] In this invention, the crosslinking agent is preferably ethylene glycol dimethacrylate, the hydrophilic monomer is preferably N-vinylpyrrolidone, and the photoinitiator is preferably TPO; The mass ratio of the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer, and photoinitiator is 1~10:70~90:0.5~2:10~30:0.5~1.5, preferably 3~8:75~85:0.8~1.7:15~25:0.7~1.3, and more preferably 5:80:1.0~1.5:20:1.0.

[0030] In this invention, the step-by-step ultraviolet curing method is as follows: first, at 3~8mW / cm 2 Irradiate at an intensity of 30-50 seconds, followed by 12-18 mW / cm². 2 Irradiate at the intensity for 60-80 seconds.

[0031] Preferably, the concentration is 4~7 mW / cm 2 Irradiate at an intensity of 35-45 seconds, followed by 13-17 mW / cm². 2 Irradiate at the intensity for 65-75 seconds.

[0032] Further optimization is achieved at 5~6 mW / cm 2 Irradiate for 40 seconds at an intensity of 14–16 mW / cm². 2 Irradiate for 70 seconds at an intensity of [insert value here].

[0033] In this invention, the solvent extraction temperature is 50~70℃, preferably 55~65℃, and more preferably 60℃; the solvent extraction time is 2~6h, preferably 2.5~5.5h, and more preferably 3~5h. The hydration treatment temperature is 4~25℃, preferably 8~20℃, and more preferably 10~15℃; the solvent extraction time is 12~48h, preferably 16~44h, and more preferably 20~40h.

[0034] The present invention also provides the application of the aforementioned composite drug microsphere-based contact lens in the preparation of a medical device for treating dry eye syndrome.

[0035] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] 20 mg of sodium hyaluronate with a molecular weight of 100 kDa was dissolved in 1 mL of deionized water as the inner aqueous phase; 10 mg of cyclosporine A and 200 mg of polylactic acid-glycolic acid copolymer (PLGA) with a molecular weight of 50,000 (the molar ratio of lactic acid to glycolic acid in PLGA is 75:25) were dissolved in 5 mL of dichloromethane as the oil phase; under ice bath conditions, the inner aqueous phase was slowly injected into the oil phase, and primary emulsification was carried out at 12,000 rpm. After 2 min, the primary emulsion (W1 / O) was obtained. The primary emulsion was emulsified a second time at 8000 rpm for 3 min in 40 mL of 2% (w / w) polyvinyl alcohol aqueous solution to form a secondary emulsion (W1 / O / W2). The secondary emulsion was then evaporated and solidified at 35 °C and 400 rpm under magnetic stirring for 12 h to evaporate the organic solvent. After solidification, the suspension was centrifuged at 4000 rpm for 10 min, the precipitate was collected, washed three times with deionized water, and freeze-dried to obtain microspheres containing the composite drug. 50 mg of microspheres were dispersed in 50 mL of 10 mM Tris-HCl buffer at pH 8.5, and 75 mg of dopamine hydrochloride was added. The surface of the microspheres was modified at 30 °C and 120 rpm. After 8 h, the reaction was completed. The microspheres were collected by centrifugation, washed with deionized water until the washing solution was colorless, and then freeze-dried to obtain polydopamine-modified microspheres, denoted as PDA@microspheres. A slurry was prepared by uniformly mixing PDA@microspheres, silicone hydrogel prepolymer, ethylene glycol dimethacrylate (EGDMA), N-vinylpyrrolidone (NVP), and photoinitiator TPO in a mass ratio of 5:80:1:20:1. The slurry was then injected into a polypropylene concave mold, air bubbles were removed, and the mixture was first heated under nitrogen protection using 5 mW / cm² gas. 2 Irradiate with high intensity ultraviolet light for 40 seconds, then use 15mW / cm 2 Irradiate with high intensity ultraviolet light for 70 seconds, and perform step-by-step ultraviolet curing to obtain a lens blank; The initial lens blank was removed from the mold and placed in anhydrous ethanol at 60°C for solvent extraction for 4 hours to remove unreacted monomers and pore-forming agents. It was then transferred to phosphate-buffered saline (PBS, pH 7.4) at 10°C for hydration treatment for 36 hours to obtain the contact lens, denoted as E1.

[0038] Example 2

[0039] Compared with Example 1, the difference is that in Example 2, the amount of sodium hyaluronate in the compound drug is 40 mg, the amount of cyclosporine A is 20 mg, the amount of PLGA is 400 mg, the amount of dopamine hydrochloride in PDA modification is 100 mg, and the amount of PDA@microspheres in lens preparation is 8 parts, the amount of silicone hydrogel prepolymer is 77 parts, and the prepared contact lens is designated as E2.

[0040] Example 3

[0041] Compared with Example 1, the difference is that in Example 3, the primary emulsification speed is 10,000 rpm and the time is 1.5 minutes; The curing temperature is 25℃, and the curing time is 20 hours; The stepped UV curing conditions are: first stage 3mW / cm 2 Irradiation for 50 seconds, second stage 12mW / cm 2 Irradiation for 80 seconds, the resulting contact lens is denoted as E3.

[0042] Comparative Example 1

[0043] Compared with Example 1, the difference is that in Comparative Example 1, the addition of dopamine hydrochloride was omitted only in the microsphere surface modification step, resulting in unmodified microspheres. The contact lenses prepared were denoted as C1.

[0044] Comparative Example 2

[0045] Compared with Example 1, the difference is that in Comparative Example 2, only 20 mg of cyclosporine A was encapsulated, sodium hyaluronate was not added, and the inner aqueous phase was replaced with an equal volume of pure water. The resulting contact lens is denoted as C2.

[0046] Comparative Example 3

[0047] Compared with Example 1, the difference is that microspheres were not prepared in Comparative Example 3. Instead, 10 mg of cyclosporine A and 20 mg of sodium hyaluronate powder were directly mixed with silicone hydrogel prepolymer, EGDMA, NVP, and TPO. The resulting contact lens was denoted as C3.

[0048] The performance of the contact lenses prepared in Examples 1-3 and Comparative Examples 1-3 was tested using the following methods: Drug loading and encapsulation efficiency determination: Cyclosporine A: High performance liquid chromatography was used. The broken lens or quantitative microspheres were accurately weighed, and the drug was completely extracted with acetonitrile. The content was determined, and the drug loading and encapsulation efficiency were calculated. Sodium hyaluronate: determined by sulfuric acid-carbazole method or enzyme-linked immunosorbent assay.

[0049] Transmittance: Measured in the visible light region (400~700nm) using a UV-Vis spectrophotometer.

[0050] Water content: Weigh the hydrated lens after wiping off surface moisture (W). wet After drying to constant weight, it is weighed (W). dry ), Moisture content = [(W wet -W dry ) / W wet ]×100%.

[0051] Oxygen permeability coefficient (Dk value): measured by polarographic method according to international standard ISO18369-4.

[0052] In vitro drug release was tested: The lens was placed in 10 mL of PBS (pH=7.4, containing 0.01% NaN3 preservative) release medium and shaken at 37℃. At preset time points (1, 2, 4, 8, 24, 48, 96, 144, 240 hours), all release medium was removed and replaced with fresh medium. The concentration of cyclosporine A in the medium at each time point was determined by HPLC, and the cumulative release curve was plotted. The release data were fitted using a classical model to analyze the release mechanism.

[0053] The test results are shown in Table 1.

[0054] Table 1. Performance test results of the contact lenses prepared in Examples 1-3 and Comparative Examples 1-3

[0055] As shown in Table 1, Examples 1-3 achieved high drug loading, and the PDA modification ensured uniform dispersion of microspheres in the matrix, with light transmittance comparable to that of blank lenses. Comparative Example 1 showed a decrease in light transmittance due to microsphere aggregation, while Comparative Example 3 showed a significant decrease in light transmittance due to direct mixing disrupting matrix homogeneity. The water content and oxygen permeability of all prepared contact lenses remained within the typical range for commercial silicone hydrogel lenses, indicating that the introduction of drug-loaded microspheres did not impair the basic function of the lenses. Only Comparative Example 3 showed slightly poorer performance due to uneven mixing. Examples 1-3 demonstrate near-ideal zero-order release kinetics, proving the key role of the core-shell structure and PDA modification layer in avoiding burst release and achieving long-term stable release. The explosive release of Comparative Example 1 and Comparative Example 3, in turn, verifies the indispensability of the PDA modification layer and the core-shell microsphere structure.

[0056] The pharmacodynamics of the animals were tested using the following methods: Dry eye model establishment: New Zealand white rabbits were selected, and scopolamine hydrobromide was injected subcutaneously, combined with exposure to dry airflow to establish a dry eye model; Grouping and drug administration: The model animals were randomly divided into a blank model group, a positive drug group (cyclosporine A eye drops), an example group (E1), and a comparative group (C1, C2, C3), and wore corresponding lenses; Therapeutic efficacy evaluation indicators: Tear secretion (Schirmer Test): Measured at different time points before and after treatment; Corneal fluorescein staining (CFS): scoring to assess the extent of corneal epithelial damage; Ocular surface inflammation index: Observe and score the conjunctival congestion and edema; Histopathology: After the experiment, eye tissue was taken for HE staining to observe the inflammatory cell infiltration and goblet cell density in the cornea and conjunctiva.

[0057] The test results are shown in Table 2.

[0058] Table 2. Results of in vivo pharmacodynamic tests after 14 days of treatment in Examples 1 and Comparative Examples 1-3.

[0059] As shown in Table 2, Example 1 demonstrated the best performance across all efficacy indicators: highest tear secretion, lowest corneal injury score (CFS) and inflammation index. Histopathological examination further confirmed its superior goblet cell density recovery effect, primarily attributed to the synergistic effect between stable anti-inflammatory drug release and continuous moisturizing with sodium hyaluronate. Comparative Example 1, due to its burst drug release, may have shown some effect initially, but it struggled to maintain a stable drug concentration over the long term, resulting in significantly inferior efficacy compared to Example 1 on day 14. This fully demonstrates the crucial role of PDA modification in maintaining long-term efficacy. Effects: Comparative Example 2 (containing only cyclosporine A) was superior to Comparative Examples 1 and 3 in terms of anti-inflammatory indicators (such as CFS and inflammatory index). However, due to the lack of immediate protection and moisturizing repair effects of sodium hyaluronate, its recovery effects on tear secretion and goblet cell density were not as good as those in Example 1, verifying the necessity of the compound drug regimen. Comparative Example 3 (direct drug mixture) had a similar therapeutic effect to positive eye drops administered multiple times daily due to rapid drug release, but it was difficult to maintain. It had the worst therapeutic effect maintenance among all groups, highlighting the decisive significance of the core-shell microsphere structure for achieving long-term treatment.

[0060] As can be seen from the above embodiments, the present invention provides a contact lens based on composite drug microspheres, its preparation method, and its application. The contact lens based on composite drug microspheres includes a lens matrix and composite drug core-shell microspheres dispersed in the lens matrix. The composite drug core-shell microspheres include a biodegradable polymer shell and a composite drug active ingredient encapsulated within the polymer shell. The composite drug active ingredient is cyclosporine A and sodium hyaluronate. The present invention, by constructing polydopamine-modified composite drug core-shell microspheres and stably integrating them into a silicone hydrogel matrix, achieves high drug loading, long-term stable and controllable release, excellent lens compatibility, and superior in vivo therapeutic effects.

[0061] 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 contact lens based on composite drug microspheres, characterized in that, The contact lens comprises a lens matrix and composite drug core-shell microspheres dispersed in the lens matrix; The composite drug core-shell microspheres include a biodegradable polymer shell and a composite drug active ingredient encapsulated within the polymer shell. The active ingredients of the compound drug are cyclosporine A and sodium hyaluronate.

2. The contact lens based on composite drug microspheres according to claim 1, characterized in that, The surface of the composite drug core-shell microspheres also includes a polydopamine modification layer.

3. The contact lens based on composite drug microspheres according to claim 1 or 2, characterized in that, The biodegradable polymer shell is a polylactic acid-glycolic acid copolymer; The lens matrix is ​​a silicone hydrogel.

4. A method for preparing a contact lens based on composite drug microspheres according to any one of claims 1 to 3, characterized in that, Includes the following steps: 1) Dissolve sodium hyaluronate in water to obtain an inner aqueous phase; dissolve cyclosporine A and microsphere framework material in an organic solvent to obtain an oil phase; add the inner aqueous phase to the oil phase for primary emulsification to obtain a primary emulsion; 2) The primary emulsion and polyvinyl alcohol aqueous solution are emulsified twice to obtain a secondary emulsion. Finally, the secondary emulsion is solidified and centrifuged to obtain microspheres. 3) Disperse the microspheres in Tris-HCl buffer, add polydopamine to modify the surface of the microspheres, and obtain modified microspheres; 4) Mix the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer and photoinitiator to obtain a slurry; 5) The slurry is injected into the mold and cured by stepwise ultraviolet light under an inert atmosphere to obtain the lens blank; 6) The initial lens blank is solvent extracted in anhydrous ethanol, and then hydrated in phosphate buffer to obtain contact lenses.

5. The method for preparing contact lenses based on composite drug microspheres according to claim 4, characterized in that, The mass-to-volume ratio of sodium hyaluronate to water is 10-50 mg: 1 mL, and the molecular weight of sodium hyaluronate is 50-200 kDa. The microsphere framework material is a polylactic acid-glycolic acid copolymer, and the molecular weight of the microsphere framework material is 10,000 to 100,000. The organic solvent is dichloromethane and / or ethyl acetate; The ratio of cyclosporine A, microsphere framework material, and organic solvent is 5~30mg:100~500mg:3~10mL.

6. The method for preparing contact lenses based on composite drug microspheres according to claim 5, characterized in that, The mass ratio of sodium hyaluronate to cyclosporine A is 10~50:5~30; The primary emulsification speed is 10,000~15,000 rpm, and the primary emulsification time is 1~3 min.

7. The method for preparing contact lenses based on composite drug microspheres according to claim 5 or 6, characterized in that, The volume ratio of the primary emulsion to the polyvinyl alcohol aqueous solution is 1:20~50, and the mass fraction of the polyvinyl alcohol aqueous solution is 1~5%. The secondary emulsification speed is 6000~10000 rpm, and the secondary emulsification time is 2~5 min; The curing temperature is 20~40℃, the curing speed is 300~600rpm, and the curing time is 4~24h; The centrifugation speed is 3000~5000 rpm, and the centrifugation time is 5~15 min.

8. The method for preparing contact lenses based on composite drug microspheres according to claim 7, characterized in that, The ratio of microspheres, Tris-HCl buffer, and polydopamine is 1 mg: 1 mL: 0.5~2.0 mg. The modification reaction is carried out at a temperature of 20-40°C, at a rotation speed of 50-200 rpm, and for a duration of 4-12 hours.

9. The method for preparing contact lenses based on composite drug microspheres according to claim 8, characterized in that, The crosslinking agent includes ethylene glycol dimethacrylate, the hydrophilic monomer includes N-vinylpyrrolidone, and the photoinitiator includes TPO; The mass ratio of the modified microspheres, silica hydrogel, crosslinking agent, hydrophilic monomer, and photoinitiator is 1~10:70~90:0.5~2:10~30:0.5~1.5; The stepped UV curing method is as follows: first, at 3~8mW / cm²... 2 Irradiate at an intensity of 30-50 seconds, followed by 12-18 mW / cm². 2 Irradiate at the intensity for 60-80 seconds; The solvent extraction temperature is 50~70℃, and the solvent extraction time is 2~6h; The hydration treatment temperature is 4~25℃, and the solvent extraction time is 12~48h.

10. The use of the contact lens based on composite drug microspheres according to any one of claims 1 to 3 in the preparation of a medical device for treating dry eye syndrome.

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