An imidazolidin ophthalmic pharmaceutical composition, its preparation method and application

Abstract

This invention discloses an imidazolidin ophthalmic pharmaceutical composition, its preparation method, and its application. The imidazolidin ophthalmic pharmaceutical composition, by weight, comprises the following components: 0.01-5 parts of an active ingredient; 0.01-55 parts of a selenium-containing organosilicon polyurethane; and 0.05-35 parts of a stabilizer. The active ingredient is imidazolidin or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer, prodrug, or deuterated form of imidazolidin. This invention overcomes the limitations of existing imidazolidin technologies, such as easy oxidation, poor stability, and high dosing frequency, providing an imidazolidin ophthalmic pharmaceutical composition with higher stability, stronger antioxidant capacity, lower dosing frequency, and better safety.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an imidazolidin ophthalmic pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Dry eye syndrome is an ocular surface disease caused by a disruption of tear film homeostasis due to various factors. Its main symptom is dryness of the eyes, accompanied by eye fatigue, itching, foreign body sensation, burning sensation, thick discharge, sensitivity to wind and light, and hypersensitivity to external stimuli. In more severe cases, the eyes may become red, swollen, congested, keratinized, and the corneal epithelium may break down with filamentous material adhering to it. Over time, this damage can lead to keratoconjunctival lesions and affect vision. Dry eye syndrome is one of the most common ocular surface diseases. Statistics show that the global prevalence of dry eye syndrome is approximately 5%–50%, with a prevalence of approximately 5%–50% in the United States and 21%–30% in China. The prevalence of dry eye syndrome gradually increases with age, especially in people over 40 years of age, where the incidence rate reaches as high as 75%. The incidence rate of dry eye syndrome is also higher in Asian populations. The "Expert Consensus on Clinical Diagnosis and Treatment of Dry Eye" states that dry eye syndrome is the most common ophthalmic disease besides myopia, with a higher incidence in women than men, and a higher incidence in the elderly than in young people. This indicates that dry eye syndrome has gradually become a common and prevalent ophthalmic disease.

[0003] Furthermore, excessive production of reactive oxygen species (ROS) in the body is associated with retinal diseases, including age-related macular degeneration (AMD), retinitis pigmentosa (RP), and glaucoma. Currently, AMD is one of the most significant causes of blindness, seriously threatening human visual health. The main pathogenic factor and characteristic of AMD is damage caused by oxidative stress in retinal pigment epithelial cells (RPE). Retinitis pigmentosa (RP) is the most common cause of blindness, characterized by progressive loss of photoreceptor cells or retinal pigment epithelial structure / function, primarily through progressive rod cell apoptosis. RP exhibits high genetic heterogeneity and a complex pathogenesis; the cause of retinal degeneration may be one or more of gene mutations, autophagy defects, or neuroinflammatory factors. The global incidence of RP is 1 / 3000–1 / 7000, with an incidence of approximately 1 / 4000 in China, and there is currently no effective treatment.

[0004] Mizoribine (MZR) is a metabolic immunosuppressant, a purine analogue that specifically inhibits the division and proliferation of rapidly growing lymphocytes, such as T cells and B cells, thereby producing an immunosuppressive effect. Based on current clinical data and further in-depth research, mizoribine has shown specific advantages in the treatment of retinitis pigmentosa-related fundus diseases (such as AMD). However, to date, there are no commercially available mizoribine-related ophthalmic products.

[0005] Ocular medication application is a long-term treatment process. However, imidazolidinedin is an imidazolidinedin nucleoside drug whose structure is easily hydrolyzed, readily decomposes in aqueous solution, and is easily oxidized and degraded under light and high temperature conditions, leading to poor drug quality and seriously affecting the drug's safety and efficacy. Therefore, there is an urgent need to provide an imidazolidinedin ophthalmic drug composition with high storage stability and guaranteed efficacy. Summary of the Invention

[0006] To address the instability and susceptibility of imidazolidin ophthalmic formulations, including their susceptibility to hydrolysis, this application proposes an imidazolidin ophthalmic pharmaceutical composition, its preparation method, and its application. This application develops an ophthalmic liquid formulation composition that improves the stability of the easily hydrolyzed drug imidazolidin while ensuring efficacy and patient comfort, enabling long-term storage of the imidazolidin formulation. The successful development of this pharmaceutical composition will have significant clinical implications and a promising market prospect, bringing benefits to patients with eye diseases.

[0007] This invention provides an ophthalmic pharmaceutical composition for imidazolidin, comprising, by weight, the following components:

[0008] The active ingredient is present in amounts of 0.01 to 5 parts, such as 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 3, 4, or 5 parts, preferably 0.02 to 3.5 parts; The amount of selenium-containing organosilicon polyurethane is 0.01 to 55 parts, such as 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 15, 30, 35, 40, 45, 50, 55 parts, preferably 0.05 to 45 parts; The stabilizer is used in amounts of 0.05 to 35 parts, such as 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, or 35 parts, preferably 0.1 to 25 parts. The active ingredient is imidazoribine or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer, crystal form, prodrug, or deuterated product of imidazoribine, wherein the isomer is a stereoisomer, tautomer, or geometric isomer.

[0009] Mizoribine (MZR), chemically known as 5-hydroxy-1-beta-D-furanosyl-1H-imidazol-5-carboxamide, inhibits purine synthesis in nucleic acid metabolism.

[0010] Polyurethane, short for polyurethane, is a general term for polymers whose molecules contain a certain amount of carbamate groups. Polyurethane can be produced by the interaction of mono- or poly-organic isocyanates (such as toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), and hexamethylene diisocyanate (HMDI)) with polyol compounds (such as polyether polyols or polyester polyols), resulting in a polymer backbone containing many repeating carbamate groups. Polyurethane polymers have good biocompatibility and physicochemical properties, especially low toxicity.

[0011] This invention utilizes selenium-containing organosilicon polyurethane as a functional pharmaceutical excipient, acting as both a surfactant and an antioxidant. Using selenium-containing organosilicon polyurethane as a surfactant not only avoids the potential toxicity, irritation, and hemolysis side effects of conventional small-molecule surfactants but also effectively improves drug solubility and stability. Furthermore, the unique viscosity and antioxidant properties of selenium-containing organosilicon polyurethane are particularly important for ophthalmic preparations, reducing irritation and prolonging the residence time of the drug solution in the eye, such as inside or on the ocular surface, thereby enhancing drug stability and therapeutic efficacy.

[0012] In some embodiments, the pharmaceutical composition of the present invention may further comprise one or more of an antibacterial agent, a thickener, and a solubilizer; the antibacterial agent is one or more of benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, chlorhexidine glucose, chlorobutanol, phenoxyethanol, methylparaben, ethylparaben, and propylparaben; the thickener is one or more of sodium hyaluronate, sodium carboxymethyl cellulose, methylcellulose, polyethylene glycol, polyvinyl alcohol, carbomer, and povidone; the solubilizer is one or more of polysorbates, polyoxyethylene castor oil glycerol ether, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, and poloxamer.

[0013] In some embodiments, the pharmaceutical composition contains water in addition to the above-described components.

[0014] In some embodiments, the pH of the pharmaceutical composition of the present invention is 5.0 to 9.0, such as 5.0 to 5.8, 5.8 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.5 or 8.5 to 9.0, preferably 5.5 to 8.5, such as 5.5, 6, 7, 8, 8.5, etc.

[0015] In some embodiments, the selenium-containing organosilicon polyurethane contains siloxane segments; preferably, the siloxane segments are polydialkylsiloxane segments, and the alkyl group can be C1-C6 alkyl; more preferably, the polydialkylsiloxane segments are polydimethylsiloxane (PDMS) segments. PDMS has excellent antioxidant properties, thermal stability, good biocompatibility, and low surface tension. Polyurethane block copolymers with PDMS as the soft segment can combine the excellent properties of both PDMS and polyurethane; most preferably, the siloxane segments are diol-based polydimethylsiloxane.

[0016] In some embodiments, the polydialkylsiloxane segment accounts for 1 to 20 wt% of the selenium-containing polydimethylsiloxane polyurethane, such as 1 to 2 wt%, 3 to 5 wt%, 6 to 10 wt%, 11 to 15 wt%, 16 to 20 wt%, etc., such as 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 20 wt%.

[0017] In some embodiments, the polydimethylsiloxane has a weight-average molecular weight of 500-5000 Da, such as 500-700 Da, 700-900 Da, 900-1000 Da, 1000-2000 Da, 2000-2500 Da, 2500 Da-3000 Da, 3000-4000 Da, or 4000-5000 Da.

[0018] In some embodiments, the selenium-containing silicone polyurethane contains polyethylene glycol (PEG) segments and / or polypropylene glycol (PPG) segments. Hydrophilic polyethylene glycol (PEG) has a higher softening temperature or melting point than PDMS, and low molecular weight polypropylene glycol (PPG) is a temperature-sensitive polymer with some hydrophilicity. Crosslinking selenium, PDMS, PEG, and PPG can prepare a selenium-containing polydimethylsiloxane polyurethane (Se-PDMS-PEG-PPG), which exhibits excellent temperature sensitivity and antioxidant properties.

[0019] In some embodiments, the weight ratio of the polyethylene glycol segments to the polypropylene glycol segments is (0.5~10):1, such as 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, etc.; preferably, the total amount of the polyethylene glycol segments and polypropylene glycol segments to the weight ratio of the polydialkylsiloxane segments is (0.3~100):1, such as 0.3:1, 0.5:1, 1:1, 3:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, etc.

[0020] In some embodiments, the weight-average molecular weight of the polyethylene glycol segments is 400-6000 Da, such as 400-600 Da, 600-800 Da, 800-1000 Da, 1000-2000 Da, 2000-3000 Da, 3000-4000 Da, 4000-5000 Da, or 5000-6000 Da.

[0021] In some embodiments, the weight-average molecular weight of the polypropylene glycol segments is 400-2000 Da, such as 400-600 Da, 600-800 Da, 800-1000 Da, or 1000-2000 Da.

[0022] In some embodiments, the polyethylene glycol and / or polypropylene glycol are oligomers, each having 10 to 20 repeating units.

[0023] In some embodiments, the selenium-containing polydialkylsiloxane polyurethane has the structural formula shown in Formula (I): ; (I) Where m = 0.1~20.5; x = 0.01~28.0; y = 0.3~30.0; z = 1.0~22.0.

[0024] In some embodiments, the pharmaceutical composition of the present invention may further comprise any one or more surfactants selected from the following: povidone, a diblock polymer polyethylene glycol-polycaprolactone, a diblock polymer selenium-polyethylene glycol-polypropylene glycol, a triblock polymer cyclodextrin-polyethylene glycol-polypropylene glycol, polyethylene glycol, polypropylene glycol, sodium hyaluronate, and hydroxypropyl methylcellulose; wherein the sodium hyaluronate is preferably sodium hyaluronate with a molecular weight of 5000-18000 Da; further, the molecular weight of polypropylene glycol or its segments is preferably 400-2000 Da. The molecular weight of polyethylene glycol or its segments is preferably 400-6000 Da. The molecular weight of the polycaprolactone segments is preferably 4000-50000 Da.

[0025] In some embodiments, the mizoribine ophthalmic pharmaceutical composition has one or more of the following characteristics: (1) The stabilizer is hydroxypropyl β-cyclodextrin, and the metal chelating agent is selected from one or more of edicarboxylic acid, calcium sodium edicarboxylic acid, disodium edicarboxylic acid, citric acid, malic acid, tartaric acid, and tryptophan, preferably citric acid; (2) The imidazolidin ophthalmic drug composition includes 0.1 to 10 parts of a pH adjuster, such as 0.1, 0.5, 1, 3, 5, 7, 9, or 10 parts, wherein the pH adjuster includes one or more of hydrochloric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, sodium citrate, and sodium hydroxide; (3) The imidazolidin ophthalmic pharmaceutical composition includes 0 to 50 parts of an osmotic pressure regulator, such as 0, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 parts, wherein the osmotic pressure regulator includes one or more of sodium chloride, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, mannitol, glycerol, propylene glycol, and glucose.

[0026] In some embodiments, the selenium-containing organosilicon polyurethane is prepared by chemically crosslinking selenium powder, a polymer containing siloxane segments, and optionally polyethylene glycol and polypropylene glycol with a polyisocyanate.

[0027] In some embodiments, the polyisocyanate is hexamethylene diisocyanate (HMDI).

[0028] In some embodiments, the polyethylene glycol and polypropylene glycol are each an oligomer independently.

[0029] In some embodiments, the preparation method of the selenium-containing organosilicon polyurethane is as follows: (a) Selenium powder, polyethylene glycol and / or polypropylene glycol, and polymers containing siloxane segments are added to a reactor and heated and dried overnight; (b) Add anhydrous toluene to the reactor for dissolution and activation; (c) After complete dissolution, concentrate by distillation using a rotary evaporator; (d) Under argon and heating conditions, toluene and the catalyst dibutyltin dilaurate were slowly injected to carry out the cross-linking reaction; when the reactants became viscous, anhydrous toluene was added to continue the cross-linking reaction to improve the yield.

[0030] (e) After reacting for 12 to 48 hours, an organic solvent is added to the reactor to quench the reaction, and the reactor is cooled at room temperature; (f) The cooled reactants are precipitated with an organic precipitant until all reactants are precipitated, and then purified to obtain the selenium-containing organosilicon polyurethane.

[0031] In some implementations, in step (a), the heating temperature is 40~46°C, such as 40, 41, 42, 43, 44, 45, 46°C.

[0032] In some embodiments, in step (b), the amount of toluene added is 20 to 30 times the total volume of the reactants, such as 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 times, etc.; the dissolution and activation process is carried out at 93 to 96°C.

[0033] In some embodiments, in step (c), the distillation temperature is 80~106°C; and the distillation is carried out to 1 / 30~1 / 5 of the volume of toluene in step (b).

[0034] In some embodiments, in step (d), the heating temperature is 90~130°C; the amount of dibutyltin dilaurate catalyst added is 1 / 20~1 / 5 of the volume of distilled toluene or the same amount as the volume of distilled toluene.

[0035] In some embodiments, in step (e), the organic solvent used for the quenching reaction is one or more of diethyl ether, ethyl acetate, acetone, butanone, dichloromethane, methanol, and acetonitrile, preferably methanol; the amount of organic solvent added is 3 to 20 times the volume of the reaction system; during the quenching reaction, anhydrous toluene may be added according to the viscosity of the reactants, and the amount of anhydrous toluene added is 7 to 10 times the current volume of the reactants.

[0036] In some embodiments, in step (f), the organic precipitant is a mixed solvent of diethyl ether and n-hexane, wherein the volume ratio of the two in the mixed solvent is 3:(1~15), such as 3:(1~4), 3:(4~8), 3:(8~10), 3:(10~5); the precipitation is performed 2~5 times; the purification process can be as follows: the solvent and crude organosilicon polyurethane are added to the reactor, stirred at 50~65℃ until the crude product is completely dissolved, heating is stopped, stirring is continued, and the mixture is allowed to cool naturally to room temperature for crystallization, and then cooled to -2~3℃ (such as -2~-1℃) and stirred for crystallization for 1~5 h to ensure complete crystallization; after crystallization, the mixture is filtered to obtain a white crystalline solid, which is dried at 50~80℃ for 8~10 h to obtain the dried final product.

[0037] In some embodiments, the weight ratio of selenium powder: polyethylene glycol and polypropylene glycol: polymer containing siloxane segments is (0.01~0.1):(1.0~10.0):(8.0~16.5).

[0038] In some embodiments, the solvent used to refine the crude product is one or more of diethyl ether, ethyl acetate, isopropanol, acetone, butanone, and dichloromethane, preferably isopropanol.

[0039] In some embodiments, the ratio of the volume (mL) of the solvent used to dissolve the crude silicone polyurethane to the weight (g) of the crude silicone polyurethane is (10~15):1.

[0040] The present invention also provides a method for preparing the aforementioned imidazolidin ophthalmic pharmaceutical composition, comprising the following steps: S1: A solution is prepared using water and selenium-containing silicone polyurethane; S2: Add imidazoribine and stabilizer to the solution described in S1, stir to dissolve and mix evenly, filter to sterilize, and obtain the pharmaceutical composition of the present invention.

[0041] In some embodiments, the specific step of S1 is as follows: placing selenium-containing organosilicon polyurethane in water for injection, dispersing it evenly, and then dissolving it at 2~8℃ for 8~12 h; In some embodiments, the preparation method further includes step S3: adding a pH adjuster and an osmotic pressure adjuster to the solution obtained in step S2, stirring to dissolve and mixing evenly, and then filtering to remove bacteria.

[0042] In some embodiments, the surfactant solution prepared in S1 can form a gel within 0.35 to 6.50 minutes at a temperature of 20 to 37°C.

[0043] The present invention also provides a pharmaceutical formulation comprising the imidazolidin ophthalmic pharmaceutical composition and packaging suitable for ophthalmic administration; said packaging being an eye drop, an intraocular injection, an ophthalmic gel, or an ophthalmic ointment.

[0044] The present invention also provides the use of the described imidazole pharmaceutical composition or the described pharmaceutical preparation in the preparation of a medicament for the prevention or treatment of eye diseases.

[0045] In some implementations, the eye diseases include, but are not limited to, any one of dry eye syndrome, corneal neovascularization, corneal fibrosis, pterygium, meibomian gland dysfunction, eye strain-related diseases, and diseases related to retinal degeneration; the diseases related to retinal degeneration include age-related macular degeneration (AMD), fundus neovascularization, and glaucoma.

[0046] In summary, compared with the prior art, the present invention achieves the following technical effects: 1. This invention overcomes the limitations of existing technologies, such as the easy oxidation of imidazoribine, poor stability, and high dosing frequency, and provides an imidazoribine ophthalmic drug composition with higher stability, stronger antioxidant capacity, lower dosing frequency, and better safety.

[0047] 2. The pharmaceutical composition of the present invention significantly reduces the frequency of administration while ensuring stable and slow drug release, resulting in a new leap in user compliance.

[0048] 3. The pharmaceutical composition of the present invention remains stable after being stored at 4-8°C for 6 months, which provides convenience for storage and use and has broad application prospects.

[0049] 4. The preparation process of the selenium-containing organosilicon polyurethane of the present invention has the following advantages: short route, readily available raw materials, simple operation, mild reaction, high yield, low cost, less waste, high safety, high purity of final product, and suitable for large-scale industrial production. Attached Figure Description

[0050] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0051] Figure 1 The 1H NMR spectrum of the SPPP prepared in Example 1 of this invention is shown.

[0052] Figure 2 The infrared spectrum of the SPPP obtained in Example 1 of this invention.

[0053] Figure 3 This is a graph showing the gelation trend of SPPP prepared in Example 1 of the present invention.

[0054] Figure 4 The results show the cell safety assessment of the SPPP prepared in Example 1 of this invention.

[0055] Figure 5 The results show the cell viability evaluation of the pharmaceutical composition in Example 3 of this invention.

[0056] Figure 6 The fluorescence spectrum is used to evaluate the adhesion ability of the pharmaceutical composition in the eye in Example 6 of this invention.

[0057] Figure 7 This is the result of the in vitro efficacy evaluation of the pharmaceutical composition in Example 6 of the present invention for treating dry eye.

[0058] Figure 8 This is the evaluation result of the antioxidant effect of the drug composition in Example 6 of the present invention in a human corneal epithelial cell oxidative stress model.

[0059] Figure 9 This is the fluorescence spectrum of the drug composition of Example 6 of the present invention stained with OGD on the corneal epithelium of a dry eye mouse model.

[0060] Figure 10 The results show the viability evaluation of retinal pigment degeneration epithelial cells using the pharmaceutical composition of Example 6 of this invention. Detailed Implementation

[0061] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. 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 should fall within the scope of protection of the present invention.

[0062] Terminology Definition In this invention, "pharmaceuticalally acceptable salt" refers to a salt formed by the reaction of a compound with a pharmaceutically acceptable inorganic or organic acid or inorganic or organic base. The inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. The organic acid includes, but is not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. The inorganic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc. The organic base includes, but is not limited to, diethylamine, triethylamine, tromethamine, glucosamine, etc.

[0063] In this invention, "pharmaceutically acceptable esters" include those esters derived from compounds that have been modified to include a carboxyl group. An in vivo hydrolyzable ester is an ester that can be hydrolyzed in a human or animal body to produce a parent acid or alcohol. Representative esters include carboxylic acid esters, wherein the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from straight-chain or branched alkyl groups (e.g., methyl, n-propyl, tert-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryl (e.g., phenoxymethyl), aryl (e.g., phenyl, optionally substituted with, for example, halogen, C1-4 alkyl, or C1-4 alkoxy, or amino); sulfonates, such as alkyl or aralkylsulfonyl groups (e.g., methanesulfonyl); or amino acid esters (e.g., L-valine or L-isoleucyl). "Pharmaceutically acceptable esters" also include inorganic esters, such as mono, di, or triphosphate esters. In these esters, unless otherwise stated, all alkyl moieties advantageously contain 1 to 18 carbon atoms, particularly 1 to 6 carbon atoms, and even more particularly 1 to 4 carbon atoms. In these esters, all cycloalkyl moieties advantageously contain 3 to 6 carbon atoms. In these esters, all aryl moieties advantageously include a phenyl group, preferably a substituted phenyl group. Therefore, pharmaceutically acceptable esters include C1-C1 alkyl groups. 22Fatty acid esters, such as acetyl, tert-butyl, or long-chain or branched unsaturated or omega-6 monounsaturated fatty acids, such as palmitoyl, stearoyl, etc. Optional aryl or heteroaryl esters include benzoyl, pyridylmethyloyl, etc., any of which can be substituted. Other pharmaceutically acceptable esters include aliphatic L-amino acid esters, such as leucyl, isoleucyl, and especially valine.

[0064] In this invention, hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, trihydrates, etc. Solvents refer to substances formed by the compounds of this invention or their pharmaceutically acceptable salts with at least one solvent molecule, including (but not limited to) methanol compounds, ethanol compounds, acetone compounds, etc.

[0065] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all materials and reagents used are commercially available.

[0066] Selenium powder: Shanghai Aladdin Biochemical Technology Co., Ltd., item number S105193, purity 99.9%.

[0067] Polyethylene glycol 2000: Shanghai Aladdin Biochemical Technology Co., Ltd., item number P103558.

[0068] Polypropylene glycol 2000: Shanghai Aladdin Biochemical Technology Co., Ltd., item number P104475.

[0069] Polydimethylsiloxane: Shanghai Aladdin Biochemical Technology Co., Ltd., item number H108691.

[0070] Hexamethylene diisocyanate: Shanghai Aladdin Biochemical Technology Co., Ltd., item number H109644.

[0071] Example 1: Preparation of Se-PDMS-PEG-PPG Using selenium powder, polyethylene glycol 2000, polypropylene glycol 2000, and polydimethylsiloxane as raw materials, a crosslinking reaction was carried out with hexamethylene diisocyanate to generate selenium-containing polydimethylsiloxane polyurethane (Se-PDMS-PEG-PPG, abbreviated as SPPP). The synthetic route is shown below:

[0072] The preparation method includes the following steps: (a) 0.05 g selenium powder, 5.0 g polyethylene glycol oligomer (Mw=2000) and polypropylene glycol oligomer (Mw=2000) in a weight ratio of 3:1, and 12.5 g polydimethylsiloxane (Mw=2500) were sequentially added to the reactor and heated and dried overnight at 42°C; (b) Add 26 times the volume of anhydrous toluene to the reactor for dissolution and activation; (c) After complete dissolution, distill the volume of toluene using a rotary evaporator until it is approximately 1 / 5 of the volume before addition; (d) Crosslinking reaction was carried out by slowly injecting 1 / 12 of the volume of distilled toluene or the same equivalent of the catalyst, dibutyltin dilaurate (DBT), under argon atmosphere and 110°C. (e) After 26 h of reaction, methanol of 1 / 6 volume of the reaction system was added to the reactor to quench the reaction and then cooled at room temperature; (f) The cooled reactants were precipitated three times with a mixed solvent of diethyl ether / n-hexane until all the reactants were precipitated, yielding crude Se-PDMS-PEG-PPG. (g) Add tetrahydrofuran solvent and crude Se-PDMS-PEG-PPG to the reactor, stir at 50~65℃ until the crude Se-PDMS-PEG-PPG is completely dissolved, stop heating, continue stirring, and allow to cool naturally to crystallize to room temperature. Then cool to -2℃ and stir to crystallize for 5 h to ensure complete crystallization. After crystallization, filter to obtain a white crystalline solid, and dry at 60℃ for 10 h to obtain the dried final product.

[0073] The products were characterized using nuclear magnetic resonance (NMR) and infrared spectroscopy. Figure 1 SPPP is shown 1 The H-NMR spectrum shows that the peak at 1.3 ppm is a characteristic peak of selenium. Figure 2 The IR spectrum of SPPP is shown, in which the absorption peak of the silicon-oxygen bond is located in the range of 1000–1200 cm⁻¹. -1 Within the wavenumber range, the absorption peak of the carbon-silicon bond is located in the range of 1000~1250 cm⁻¹. -1 Within the wavenumber range, this indicates that polysiloxane segments have been introduced into the polyurethane molecular chain.

[0074] Example 2: SPPP Preparation Condition Test Based on the SPPP preparation conditions of Example 1, the conditions of activation reaction, crosslinking reaction, quenching reaction, precipitation reaction and purification during the preparation process were investigated.

[0075] (1) Investigation of activation reaction conditions Activation reaction 1: Add 0.05 g of selenium powder, 5 g of a mixture of polyethylene glycol oligomer (Mw=2000) and polypropylene glycol oligomer (Mw=2000) (3:1), 0.3 g of polydimethylsiloxane (Mw=2500), and 50 mL of anhydrous toluene to the reaction flask in sequence. Heat and stir at 60°C for 1 hour. If there is insoluble matter, start heating. Starting from 80°C, increase the temperature by 5°C every 10 minutes and record the dissolution temperature.

[0076] Activation reaction 2: 0.05 g selenium powder, 5 g of a mixture of polyethylene glycol oligomer and polypropylene glycol oligomer (3:1), 0.3 g of polydimethylsiloxane, and 100 mL of anhydrous toluene were added sequentially to the reaction flask. The mixture was heated and stirred at 60°C for 1 hour. When insoluble matter was found, heating was started. Starting at 80°C, the temperature was increased by 5°C every 10 minutes. The dissolution temperature was recorded and shown in Table 1.

[0077] Table 1. Parameters for investigating the amount of solvent and dissolution temperature in the activation reaction.

[0078] Note: The yield calculation formula is: Yield = Actual mass of purified and dried product / Theoretical product mass × 100%.

[0079] As shown in Table 1, the reaction produces insoluble substances at low temperatures. Adding 10 times the amount of toluene requires heating the reaction solution to 103-105℃ to dissolve the substances, but the dissolution temperature is too high. Adding 20 times the amount of toluene requires heating the reaction solution to 93-96℃ to dissolve the substances completely, and the dissolution temperature is suitable. Considering cost, energy consumption, and other factors, the method of adding 20 times the amount of toluene and dissolving at 93-96℃ is adopted.

[0080] (2) Investigation of cross-linking reaction conditions Crosslinking reaction 1: Add 5 g of a mixture of polyethylene glycol oligomer (Mw=2000) and polypropylene glycol oligomer (Mw=2000) (weight ratio 3:1), 0.1 g of polydimethylsiloxane, and 100 mL of anhydrous toluene to a reaction flask. After dissolving and activating the mixture by heating at 93~96℃, continue heating at 105℃ under argon atmosphere. Add 0.2 mg of HMDI and an equivalent amount of catalyst DBT to carry out the crosslinking reaction.

[0081] Crosslinking reaction 2: Add 5 g of a mixture of polyethylene glycol oligomer (Mw=2000) and polypropylene glycol oligomer (Mw=2000) (weight ratio 3:1), 0.1 g of polydimethylsiloxane, and 100 mL of anhydrous toluene to the reaction flask. After dissolving and activating by heating at 93~96℃, continue heating at 108℃ under argon atmosphere, and add 0.2 mg of HMDI and an equivalent amount of catalyst DBT to carry out the crosslinking reaction.

[0082] Crosslinking reaction 3: Add 5 g of a mixture of polyethylene glycol oligomer (Mw=2000) and polypropylene glycol oligomer (Mw=2000) (weight ratio 3:1), 0.1 g of polydimethylsiloxane, and 100 mL of anhydrous toluene to the reaction flask. After dissolving and activating by heating at 93~96℃, continue heating at 110℃ under argon atmosphere, and add 0.2 mg of HMDI and an equivalent amount of catalyst DBT to carry out the crosslinking reaction.

[0083] The yields are calculated and shown in Table 2.

[0084] Table 2. Gradient of heating temperature for crosslinking reaction

[0085] As shown in Table 2, the crosslinking reaction was carried out at 110℃, resulting in a higher yield.

[0086] Crosslinking reaction 4: Add 5 g of a mixture of polyethylene glycol and polypropylene glycol oligomers, 0.1 g of polydimethylsiloxane, and 100 mL of anhydrous toluene to a reaction flask. After dissolving and activating the mixture by heating at 93-96°C, continue heating at 110°C under argon atmosphere. Add 0.2 mg of HMDI and an equivalent amount of catalyst to carry out the crosslinking reaction. When the reactants become viscous, add another 10 mL of anhydrous toluene to continue the crosslinking reaction.

[0087] Crosslinking reaction 5: Add 5 g of a mixture of polyethylene glycol and polypropylene glycol oligomers, 0.1 g of polydimethylsiloxane, and 100 mL of anhydrous toluene to a reaction flask. After dissolving and activating the mixture by heating at 93-96°C, continue heating at 110°C under argon atmosphere. Add 0.2 mg of HMDI and an equivalent amount of catalyst to carry out the crosslinking reaction. When the reactants become viscous, add another 20 mL of anhydrous toluene to continue the crosslinking reaction.

[0088] The yields are calculated and shown in Table 3.

[0089] Table 3. Amount of anhydrous toluene added during the crosslinking reaction

[0090] As shown in Table 3, when the reactants become viscous, continuing to add anhydrous toluene to carry out the cross-linking reaction can increase the yield.

[0091] (3) Investigation of quenching reaction conditions Quenching reaction 1: After the crosslinking reaction for 24 h, 3 mL of methanol was added to quench the reaction mixture, and the mixture was cooled to room temperature to obtain the reaction mixture.

[0092] Quenching reaction 2: After the crosslinking reaction for 24 h, 8 mL of methanol was added to quench the reaction mixture, and the mixture was cooled to room temperature to obtain the reaction mixture.

[0093] The yields were calculated and are shown in Table 4.

[0094] Table 4. Quenching solvent addition amount after quenching reaction

[0095] As shown in Table 4, the reaction product yield was higher when 8 mL of methanol was added after 24 h of cross-linking reaction.

[0096] (4) Investigation of precipitation reaction conditions Precipitation reaction 1: 40 mL of acetone was added to the cooled reaction mixture to precipitate the product, yielding crude Se-PDMS-PEG-PPG. 2.10 g of product was obtained, with a yield of 80%.

[0097] Precipitation reaction 2: 40 mL of diethyl ether was added to the cooled reaction mixture to precipitate the product, yielding crude Se-PDMS-PEG-PPG. 2.27 g of product was obtained, with a yield of 92%.

[0098] The results of precipitation reactions 1 and 2 show that the reaction mixture precipitates better in diethyl ether, so we will continue to screen using diethyl ether as the base solvent.

[0099] Precipitation reaction 3: 40 mL of diethyl ether / n-hexane (volume ratio 3:1) was added to the cooled reaction mixture to precipitate the product, yielding crude Se-PDMS-PEG-PPG.

[0100] Precipitation reaction 4: 40 mL of diethyl ether / n-hexane (volume ratio 3:4) was added to the cooled reaction mixture to precipitate the product, yielding crude Se-PDMS-PEG-PPG.

[0101] Precipitation reaction 5: 40 mL of diethyl ether / n-hexane (volume ratio 3:8) was added to the cooled reaction mixture to precipitate the product, yielding crude Se-PDMS-PEG-PPG.

[0102] The yields were calculated and are shown in Table 5.

[0103] Table 5. Effect of precipitation solvent gradient on yield

[0104] As shown in Table 5, the yield is higher when the ratio of diethyl ether to n-hexane is 3:8.

[0105] (5) Examination of refining conditions 14.8 g of crude Se-PDMS-PEG-PPG and 148 mL of isopropanol were added sequentially to a reaction flask. The mixture was heated, stirred, and refluxed. Starting with 148 mL of isopropanol (10 times the volume), 1 times the volume (14.8 mL) of isopropanol was added every 30 minutes until the solid was completely dissolved. Heating was stopped, and the mixture was allowed to cool naturally to room temperature. Then, the temperature was further lowered to 0–3 °C, and crystallization was allowed to occur for approximately 1 hour. The mixture was then filtered to obtain high-purity selenium-containing polydimethylsiloxane polyurethane (Se-PDMS-PEG-PPG). The results are shown in Table 6.

[0106] Table 6 Refining Solvent Amount Gradient

[0107] 10.2 g of crude Se-PDMS-PEG-PPG and 133 mL of isopropanol were added sequentially to a reaction flask. The mixture was heated, stirred, and refluxed until the solid dissolved. Heating was then stopped, and the mixture was allowed to cool naturally to room temperature. The temperature was then further reduced to 0–3 °C or -2–-1 °C, and crystallization was allowed to occur for approximately 1 hour. The mixture was then filtered to obtain high-purity selenium-containing polydimethylsiloxane polyurethane (Se-PDMS-PEG-PPG). The results are shown in Table 7.

[0108] Table 7 Refining Crystallization Temperature Parameters

[0109] As shown in Table 7, crystallization occurs in the range of -2 to -1℃, with a higher yield than in the range of 0 to 3℃.

[0110] Example 3 SPPP Performance Test (1) SPPP temperature sensitivity test: Experimental method: 12wt%, 14wt% and 16wt% SPPP solutions were prepared with PBS solution and placed at 0℃, 4℃, 8℃, 16℃ and 25℃ for 10 minutes respectively. Then they were placed in a water bath at 37℃ and the gel transformation was observed every 20 seconds.

[0111] The results are as follows Figure 3 As shown, the temperature sensitivity of SPPP solution varies with the initial temperature. Three SPPP solutions of different concentrations were heated from different initial temperatures to 37°C. The higher the sample concentration and the higher the initial temperature, the shorter the time required to reach 37°C. SPPP exhibits excellent in-situ gelation properties in response to human ocular surface temperature. It is a flowing liquid at room temperature, facilitating eye drop administration, and rapidly forms a gel upon contact with the ocular surface at 37°C, thus prolonging the retention time of the drug solution on the ocular surface.

[0112] (2) Effects of SPPP on cell viability: HCEs (human corneal epithelial cells) were cultured to a suitable state, digested with trypsin, and then adjusted to a concentration of 10.4 Cell count was determined by seeding cells into 96-well plates and incubating for 12 h. Cells were then treated with different concentrations of SPPP solution (0, 12.5, 25, 50, 100, 200 μg / mL). After 24 h, the culture medium was discarded, and 10 μg / mL MTT solution was added to each well. After incubation for 4 h, the medium was discarded, and 10 μL DMSO solution was added to each well until completely dissolved.

[0113] The results are as follows Figure 4 As shown, different concentrations of SPPP solution had almost no effect on the viability of HCE cells, indicating that SPPP has good safety. This demonstrates that SPPP is non-cytotoxic to human corneal epithelium, exhibits excellent biocompatibility, and meets the high safety requirements for ophthalmic excipients.

[0114] (3) Evaluation of SPPP adhesion ability: After anesthetizing C57BL / 6J mice, 2 µL of 0.1% free rhodamine B, 0.1% rhodamine B in F127 solution, and 0.1% rhodamine B in SPPP solution were instilled. The changes in fluorescence intensity on the mouse ocular surface were recorded at different time points (10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 120 min, and 150 min) using a stereofluorescence microscope.

[0115] The results are as follows Figure 5 As shown, compared with free rhodamine B and F127 solution containing the same concentration of rhodamine B, SPPP solution containing the same concentration of rhodamine B has stronger adhesion to the ocular surface, which can significantly reduce drug loss through blinking, reduce the frequency of daily administration, and improve patient medication compliance.

[0116] Example 4: Preparation of a test solution containing imidazolidin Test solutions 1 to 5: Mix imidazoribine, SPPP, sodium sulfite, and citric acid according to the formulation in Table 8, and add water for injection to the mixture to dissolve it. Adjust the pH of the aqueous solution to 5.8 using 0.1M sodium hydroxide solution or dilute hydrochloric acid solution as a pH adjuster, and add water for injection to the prescribed volume. Filter these solutions sterilely through a 0.22 μm filter, and then seal them in sterile vials for use as test solutions.

[0117] The components of test solutions 6 and 7, used as comparisons, are shown in Table 9. Imidazolidin, sodium sulfite, citric acid, and disodium edetate were mixed, and water for injection was added to the mixture to dissolve them. The pH of the aqueous solution was adjusted to 5.8 using 0.1M sodium hydroxide solution or dilute hydrochloric acid solution as a pH adjuster, and water for injection was added to the prescribed volume. These solutions were sterile filtered through a 0.22 μm filter and then sealed in sterile vials for use as test solutions.

[0118] Table 8 Composition of test solutions 1-5

[0119] Table 9 Composition of test solutions 6-7

[0120] Example 5: Stability Testing of Test Solution Stability tests were performed on test solutions 1–7. The test solutions were stored under high temperature (60°C), high temperature (40°C), light exposure (12000 Lux ± 5000 Lux), and low temperature (4–8°C), respectively. The degradation products of the test solutions under different conditions were analyzed by high performance liquid chromatography (HPLC).

[0121] Referring to the quality standard of imidazoribine as listed in the Japanese Pharmacopoeia (JP), the detection method is as follows: Accurately weigh approximately 0.1 g of imidazoribine and dissolve it in 50 mL of mobile phase. Add 5 mL of this solution to the mobile phase, and then add more mobile phase to accurately prepare 50 mL of solution. Use this solution as the sample solution. Accurately weigh approximately 10 mg of imidazoribine standard reference, dissolve it in the mobile phase to prepare 50 mL of solution, and use this solution as the standard solution. Test with 5 mL of each sample solution and standard solution, and determine the peak area of ​​imidazoribine in each solution.

[0122] Operating conditions: Detector: UV-Vis spectrophotometer (wavelength: 279 nm); Column: stainless steel column, inner diameter 4.6 mm, length 25 cm, packed with octadecylsilane-bonded silica gel (particle size 5 mm); Column temperature: constant temperature approximately 25℃; Mobile phase: diluted phosphoric acid (1 / 1500); Flow rate: adjusted to allow imidazolidin residence time of approximately 9 minutes.

[0123] The test results are shown in Table 10. Table 10 Stability test results under different conditions

[0124] As shown in Table 10, the imidazolidin ophthalmic drug composition remained stable after being stored at 4-8°C for 6 months, with individual decomposition products not exceeding 2% and the total decomposition products not exceeding 5.5%. Compared with the control formulation without SPPP, the imidazolidin ophthalmic composition of this invention with added selenium-containing organosilicon polyurethane SPPP showed significantly improved antioxidant and hydrolytic stability; the degree of drug degradation was extremely low after long-term storage at 4-8°C, indicating that SPPP can improve the stability of imidazolidin aqueous solution, providing convenience for the storage and use of imidazolidin ophthalmic drugs.

[0125] Example 6: Evaluation of the therapeutic effect of dry eye syndrome (1) Effects of the drug composition on cell viability: Cell viability was assessed using CCK-8 assay: HCECs were seeded in 96-well plates (approximately 10 cells / well per well). 4 Cell count: 100 µL of culture medium (serum-free) per well, incubated at 37°C in a 5% CO2 incubator. Once the cells reach the optimal experimental density (70%–80% cell confluence), culture medium containing different concentrations of the drug (prepared in test solution 2, based on imidazoribine concentration) was added to each well and incubated for 24 h. After incubation, the culture medium was discarded. The cells were washed once with 1×PBS and discarded. 100 µL of prepared CCK-8 solution was added to each well (10 µL of CCK-8 solution was added to 90 µL of culture medium and mixed thoroughly; it should be prepared fresh and protected from light). The cells were incubated at 37°C for 4 h. After incubation, the absorbance at 450 nm was measured and recorded for each well using a microplate reader.

[0126] The results are as follows Figure 6 As shown, when the concentration of the imidazolidin compound preparation is ≤62.5 μg / mL, the HCE cell viability is close to 100% and there is no cytotoxicity; when the concentration is >125 μg / mL, the cell viability decreases significantly. The clinically safe dosage concentration can be controlled within 62.5 μg / mL.

[0127] (2) Evaluation of the efficacy of the drug composition in treating dry eye: Oxidative stress and inflammation were induced in HCEC cells using 300 µM H2O2. HCEC cells were cultured at 5 × 10⁶ cells per well. 5 The cells were seeded at a density of 100 μM into six-well plates and incubated overnight to allow for adhesion. HCEC cells were pre-incubated for 8 hours with 300 µM H2O2 solution and 1 mL of the corresponding drug (samples 1, 2, 3, and 4, with the same formulations as test solutions 2, 3, 4, and 5 above). Then, the expression of IL-6 and IL-8 in the cells was detected by qPCR.

[0128] The results are as follows Figure 7 As shown, compared with the control group, H2O2 induced a significant increase in the expression levels of IL-6 and IL-8. By adding drugs with different formulations, the increase in IL-6 and IL-8 induced by H2O2 in HCEC cells can be significantly reduced, which can inhibit the inflammatory response induced by corneal epithelial oxidative stress and is suitable for the repair of inflammatory damage in dry eye.

[0129] (3) Changes in reactive oxygen species production in human corneal epithelial cells: The antioxidant effects of the pharmaceutical excipient SPPP and imidazolidin ophthalmic drug combination were tested using human corneal epithelial cells.

[0130] The experimental design included a blank control group (CTRL), a model group (H2O2), a blank excipient group (H2O2+ACCESSORY), a free imidazoribine group (H2O2+MZR), and an imidazoribine drug composition group (H2O2+MZRCOMPOSITION, solution 2). Human corneal epithelial cells were cultured at 10 μg / well. 4 Cells were seeded at a density of / cells into six-well plates and incubated overnight to allow adhesion. Different groups were incubated with 1 mL of the corresponding drug for 4 hours, followed by DCFH-DA fluorescent staining.

[0131] The results are as follows Figure 8 As shown, DCFH-DA fluorescence staining of human corneal epithelial cells revealed that the functional pharmaceutical excipient SPPP and the ophthalmic drug composition of imidazolidin exhibited significant antioxidant properties, effectively reducing reactive oxygen species production in a hydrogen peroxide-induced oxidative stress model of human corneal epithelial cells, and was superior to the imidazolidin control group.

[0132] (4) Changes in OGD staining of corneal epithelium in a dry eye mouse model before and after drug administration A dry eye model was established in 6-8 week old C57BL / 6 mice by subcutaneous injection of scopolamine (4 times / day) combined with a dry environment for 7 days. The mice were then divided into four groups: a blank control group (CTRL), a model group (H2O2), a blank excipient group (H2O2+ACCESSORY), a free imidazoribine group (H2O2+MZR), and an imidazoribine drug composition group (H2O2+MZR COMPOSITION, test solution 2). Mice in each group were given the corresponding drug eye drops (blank excipient, free imidazoribine, and imidazoribine drug composition group) twice / day. After 7 days of treatment, corneal OGD staining was performed.

[0133] Corneal OGD staining results as follows Figure 9 As shown, the imidazoribine drug combination group (test solution 2) can reduce corneal epithelial damage in a dry eye mouse model, significantly reduce corneal OGD staining, and is superior to the imidazoribine control group.

[0134] (5) Effect of the drug composition on the viability of retinal pigment degeneration epithelial cells Using test solution 5 as the sample, after dilution (based on the content of imidazoribine, 1, 10, 100, 1000 μg / mL), the viability of retinitis pigmentosa epithelial cells was detected by CCK-8 assay. The experimental method is as follows: Retinitis pigmentosa epithelial cells were seeded in 96-well plates (approximately 10 cells per well). 4Cells were incubated at 37°C in a 5% CO2 incubator with 100 µL of serum-free culture medium per well until the cells reached the optimal experimental density (70%–80% cell confluence). Then, culture medium containing different concentrations of the drug (1, 10, 100, and 1000 μg / mL) was added and incubated for 24 h. After incubation, the culture medium was discarded. The cells were washed once with 1×PBS and discarded. 100 µL of prepared CCK-8 solution was added to each well (10 µL of CCK-8 solution was added to 90 µL of culture medium and mixed thoroughly; it should be prepared immediately and protected from light). The cells were incubated at 37°C for 4 h. After incubation, the absorbance at 450 nm was measured and recorded for each well using a microplate reader.

[0135] The results are as follows Figure 10 As shown, when the concentration of imidazoribine is 10 μg / mL, it can significantly inhibit the activity of retinitis pigmentosa epithelial cells.

[0136] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A mizoribine ophthalmic pharmaceutical composition, characterized in that, It contains the following components in parts by weight: 0.01 to 5 parts of active ingredient; 0.01 to 55 parts of selenium-containing organosilicon polyurethane; Stabilizer 0.05~35 parts; The active ingredient is imidazoribine or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer, crystal form, prodrug, or deuterated form of imidazoribine.

2. The imidazolidin ophthalmic pharmaceutical composition according to claim 1, characterized in that, The selenium-containing organosilicon polyurethane contains siloxane segments; Preferably, the siloxane segment is a polydialkylsiloxane segment; Preferably, the alkyl group is a C1-C6 alkyl group.

3. The imidazolidin ophthalmic pharmaceutical composition according to claim 2, characterized in that, The percentage of the polydialkylsiloxane segment in the selenium-containing polydimethylsiloxane polyurethane is 1~20wt%.

4. The imidazolidin ophthalmic pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The selenium-containing organosilicon polyurethane contains polyethylene glycol segments and / or polypropylene glycol segments.

5. The imidazolidin ophthalmic pharmaceutical composition according to claim 4, characterized in that, The weight ratio of the polyethylene glycol segment to the polypropylene glycol segment is (0.05~10):1; Preferably, the total amount of polyethylene glycol segments and polypropylene glycol segments is in a weight ratio of (0.3~100):1 to the weight of polydialkylsiloxane segments.

6. The imidazolidin ophthalmic pharmaceutical composition according to claim 1, characterized in that, The structure of the selenium-containing polydialkylsiloxane polyurethane is shown in Formula (I): ； （Ⅰ） Where m = 0.1~20.5; x = 0.01~28.0; y = 0.3~30.0; z = 1.0~22.

0.

7. The imidazolidin ophthalmic pharmaceutical composition according to claim 1, characterized in that, The imidazolidin ophthalmic pharmaceutical composition further includes any one or more surfactants selected from the following: povidone, biblock polymer polyethylene glycol-polycaprolactone, biblock polymer selenium-polyethylene glycol-polypropylene glycol, triblock polymer cyclodextrin-polyethylene glycol-polypropylene glycol, polyethylene glycol, polypropylene glycol, sodium hyaluronate, and hydroxypropyl methylcellulose.

8. The imidazolidin ophthalmic pharmaceutical composition according to claim 1, characterized in that, It has one or more of the following characteristics: (1) The stabilizer is hydroxypropyl β-cyclodextrin, and the metal chelating agent is selected from one or more of edicarboxylic acid, calcium sodium edicarboxylic acid, disodium edicarboxylic acid, citric acid, malic acid, tartaric acid, and tryptophan; (2) The imidazolidin ophthalmic drug composition includes 0.1 to 10 parts of a pH adjuster, wherein the pH adjuster includes one or more of hydrochloric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, sodium citrate, and sodium hydroxide; (3) The imidazolidin ophthalmic pharmaceutical composition includes 0 to 50 parts of an osmotic pressure regulator, wherein the osmotic pressure regulator includes one or more of sodium chloride, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, mannitol, glycerol, propylene glycol, and glucose.

9. The imidazolidin ophthalmic pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The preparation method of the selenium-containing organosilicon polyurethane is as follows: using selenium powder, a polymer containing siloxane segments, and optionally polyethylene glycol and polypropylene glycol as raw materials, chemically crosslinking them with a poly-organic isocyanate.

10. The imidazolidin ophthalmic pharmaceutical composition according to claim 9, characterized in that, The specific preparation method of the selenium-containing organosilicon polyurethane is as follows: (a) Selenium powder, polymers containing siloxane segments, polyethylene glycol and / or polypropylene glycol are added to a reactor and heated and dried overnight; (b) Add anhydrous toluene to the reactor for dissolution and activation; (c) After complete dissolution, concentrate by distillation using a rotary evaporator; (d) Under argon and heating conditions, toluene and the catalyst dibutyltin dilaurate were slowly injected to carry out a crosslinking reaction; (e) After reacting for 12 to 48 hours, an organic solvent is added to the reactor to quench the reaction, and the reactor is cooled at room temperature; (f) The cooled reactants are purified by precipitation with an organic precipitant to obtain the selenium-containing organosilicon polyurethane.

11. A method for preparing the imidazolidin ophthalmic pharmaceutical composition according to any one of claims 1 to 10, characterized in that, Includes the following steps: S1: A solution is prepared using water and selenium-containing silicone polyurethane; S2: Add imidazolidin and stabilizer to the solution described in S1, stir to dissolve and mix evenly, filter to sterilize, and obtain the imidazolidin ophthalmic drug composition.

12. A pharmaceutical preparation, characterized in that, The ophthalmic pharmaceutical composition comprising any one of claims 1 to 10 and packaging suitable for ophthalmic administration; The packaging is for eye drops, intraocular injections, ophthalmic gels, or ophthalmic ointments.

13. The use of the imidazole pharmaceutical composition according to any one of claims 1 to 10 or the pharmaceutical preparation according to claim 12 in the preparation of a medicament for the prevention or treatment of eye diseases.

14. The application according to claim 13, characterized in that, The eye disease mentioned is any one of the following: dry eye syndrome, corneal neovascularization, corneal fibrosis, pterygium, meibomian gland dysfunction, eye strain-related diseases, and diseases related to retinal degeneration.

Images