Ophthalmic gel preparation and preparation method thereof

Abstract

The invention discloses an ophthalmic gel preparation and a preparation method thereof, and belongs to the field of ophthalmic administration. The preparation is prepared from the following components in percentage by mass: 13 to 26 percent of temperature-sensitive gelling polymer, 0.05 to 0.30 percent of ion-sensitive gelling polysaccharide, 0.02 to 0.20 percent of aldehyde polysaccharide, 0.05 to 0.50 percent of amino polymer, 0.01 to 2.00 percent of buffer system, 0.10 to 2.00 percent of isoosmotic adjusting agent and the balance of water, and the aldehyde polysaccharide and the amino polymer form an imine bond dynamic cross-linked network. The preparation method comprises the steps of low-temperature dissolution, mixing, pH adjustment, sterilization and filling. The preparation is good in flowability when being dropped, can be quickly gelatinized and self-recovered under the action of temperature and tear ions after entering eyes, improves the controllability of ocular surface retention and drug release, and can be used for packaging without bacteriostatic agents.

Description

Technical Field

[0001] This invention relates to the field of ophthalmic drug delivery technology, and particularly to an ophthalmic gel formulation and its preparation method. Background Technology

[0002] Topical ophthalmic drug administration is most commonly done in the form of eye drops, which are convenient to use and have a rapid onset of action. However, the eye has multiple physiological barriers and dynamic clearance mechanisms (such as tear dilution, blink shearing, and nasolacrimal drainage), which result in a short residence time of the drug in front of the cornea and limited effective penetration. This leads to low bioavailability of topical drugs and difficulty in reducing the frequency of administration.

[0003] To address the aforementioned issues, existing technologies typically extend the contact time between the drug and the ocular surface and improve drug release behavior by increasing formulation viscosity, using ointments / gels, ophthalmic inserts, contact lens drug delivery systems, or introducing nanocarriers. Among these, ophthalmic in-situ gels have become an important technological approach due to their characteristics of "good fluidity when instilled and transformation into a gel upon entering the eye under environmental stimuli." Common triggering mechanisms for this type of system include temperature-sensitive, ion-sensitive, and pH-sensitive mechanisms, and they can be combined with nanodelivery systems to further enhance retention and controlled release performance. However, existing ophthalmic thickening or gel systems still have certain limitations: on the one hand, to obtain sufficient gel strength and retention time, it is often necessary to increase the amount of gelling agent or strengthen the network structure, which can easily lead to user experience problems such as visual interference, foreign body sensation, or temporary eye smearing; on the other hand, under conditions of continuous tear film dilution and shearing, in-situ gels with a single stimulus response may encounter difficulties in simultaneously achieving optimal gelation rate, gel stability, and release profile. For poorly soluble active ingredients, relying solely on thickeners / mono-network gels may lead to undesirable phenomena such as insufficient solubilization capacity, precipitation during storage, or rapid release before and slow release afterward, which in turn affect the stability and reproducibility of therapeutic efficacy.

[0004] Furthermore, ophthalmic preparations often employ multi-dose packaging for long-term, repeated use. To inhibit microbial contamination during use, multi-dose eye drops traditionally contain antimicrobial agents. Quaternary ammonium salt antimicrobial agents, such as benzalkonium chloride, have been extensively discussed in relation to ocular surface irritation, epithelial cell toxicity, and the associated risks of ocular surface diseases. Therefore, the clinical and market demand for antimicrobial agents-free or low-exposure antimicrobial agents continues to grow. However, in the absence of antimicrobial agents, multi-dose packaging relies on structural designs such as anti-backflow valves and filters / ventilations to reduce contamination risks. This makes the device and process complex to implement, and issues such as "in-use contamination of the dropper tip / bottle opening" have been repeatedly highlighted in the literature, further increasing the difficulty of co-designing the formulation and packaging.

[0005] Therefore, how to construct ophthalmic gel formulations and their preparation methods that combine temperature-sensitive gelling polymers, ion-sensitive gelling polysaccharides, and aldehyde-amino polymer dynamic crosslinking networks, so as to improve ocular surface retention and drug release controllability while maintaining good drop flowability and reducing the risk of antibacterial agent-related irritation, is a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0006] To address the shortcomings of the existing technology, this invention provides an ophthalmic gel formulation and its preparation method. Through the synergistic effect of a dynamic cross-linked network composed of a temperature-sensitive gelling polymer, an ion-sensitive gelling polysaccharide, and an aldehyde-modified polysaccharide-amine polymer, the ophthalmic gel formulation maintains its fluidity while improving the controllability of ocular surface retention and drug release. The ophthalmic gel formulation of this invention can also be used in conjunction with single-dose packaging without antibacterial agents or multi-dose packaging with anti-backflow structures to reduce the risk of antibacterial agent-related irritation while ensuring sterility and safety.

[0007] In a first aspect, the present invention provides an ophthalmic gel formulation, characterized in that, by weight percentage, the ophthalmic gel formulation comprises the following raw materials: Temperature-sensitive gelling polymers: 13–26 wt% Ion-sensitive gelling polysaccharide 0.05–0.30 wt%; Aldehyde-modified polysaccharides: 0.02–0.20 wt%; Amine polymer 0.05–0.50 wt%; The buffer system components range from 0.01 to 2.00 wt%. Isotonic conditioner 0.10–2.00 wt%; The remainder is water; The aldehyde-modified polysaccharide and the amino polymer form an imine bond crosslinking network through the condensation of aldehyde and amino groups; the ophthalmic gel formulation is obtained by mixing and dissolving the raw materials and adjusting the pH.

[0008] In the above technical solution, temperature-sensitive gelling polymers and ion-sensitive gelling polysaccharides together constitute the basic network for in-situ gelation: the formulation exists in a highly fluid solution form at the preparation and storage temperatures, facilitating precise dropwise addition; when dropped onto the ocular surface, due to the ocular surface temperature and the tear ion environment, the temperature-sensitive gelling polymer aggregates and its viscosity increases, while the ion-sensitive gelling polysaccharides form or enhance a three-dimensional network under ion intervention, transforming the system from a solution state into a gel layer with a certain strength and adhesion. The aldehyde-modified polysaccharide and the amino polymer form an imine bond crosslinking network through the condensation of aldehyde and amino groups. This type of dynamic covalent bond can partially break under shear action to facilitate shear thinning and spreading, and can reform the crosslinked structure after the external force is removed, thus endowing the gel with good structural resilience and long-term stability.

[0009] The buffer system components and isotonic regulators are used to control the pH and osmotic pressure of the formulation within a range close to the physiological environment of the ocular surface. This ensures the stability of the active ingredients and polymer network in the system while reducing the risk of irritation to the cornea and conjunctiva. Through the synergistic effect of the above component ratios and network structure, the ophthalmic gel formulation maintains low viscosity and good fluidity during the instillation stage. After entering the ocular surface environment, it rapidly forms a gel layer with temperature-responsive, ion-responsive, and dynamic cross-linking properties. This effectively improves the retention time and adhesion of the formulation on the ocular surface, improves the contact and penetration conditions between the active ingredients and ocular surface tissues, and slows down the release rate of the active ingredients. Thus, it enhances the duration of efficacy and the comfort of use without significantly increasing the burden of medication.

[0010] Preferably, the temperature-sensitive gelling polymer includes one or more of the following: polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer, and cellulose ethers that exhibit temperature-sensitive gelation behavior in an aqueous phase.

[0011] More preferably, the temperature-sensitive gelling polymer includes poloxamer block copolymers and / or poloxamer-amine block copolymers; the poloxamer block copolymers include one or more of poloxamer 407, poloxamer 188, poloxamer 338, and poloxamer 403; the poloxamer-amine block copolymers include polyoxyethylene-polyoxypropylene-ethylenediamine block copolymers with temperature-sensitive gelling behavior.

[0012] Preferably, the ion-sensitive gelling polysaccharide includes anionic polysaccharides capable of forming or enhancing a gel network in the presence of sodium, potassium, and / or calcium ions, wherein the anionic polysaccharide includes one or more of gellan gum, deacetylated gellan gum, alginate and its sodium or calcium salts, K-carrageenan, and low-methoxyl pectin. Preferably, the amine polymer includes one or more of amino-modified sodium hyaluronate, amino-modified potassium hyaluronate, chitosan, quaternized chitosan, and gelatin derivatives; the amine content of the amine polymer is 0.05–2.00 mmol / g.

[0013] In the above technical solutions, by expanding and defining temperature-sensitive gelling polymers, ion-sensitive gelling polysaccharides, and amine polymers, the in-situ gelling system exhibits better adaptability and stability in material selection. The temperature-sensitive gelling polymers utilize polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymers, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymers, and cellulose ethers with temperature-sensitive gelation behavior. These polymers can undergo reversible sol-gel transitions in the aqueous phase with temperature changes. Specifically, poloxamer and poloxamine block copolymers form micelles through the aggregation of hydrophobic blocks under heating conditions, which further accumulate into a network structure. This allows for rapid thickening or gelation at ocular surface temperatures while maintaining the fluidity of the formulation during the drop application stage. The cellulose ether materials help to smooth out system viscosity changes, improve the uniformity and stability of the gelation process, and thus enhance user comfort.

[0014] Ion-sensitive gelling polysaccharides are selected from anionic polysaccharides that can form or enhance gel networks in the presence of sodium, potassium, and / or calcium ions. This allows the formulation to further strengthen the gel structure upon contact with the tear environment, aided by the action of ions in the tear film. Gellan gum and its deacetylated forms are beneficial for forming gel networks with high transparency and moderate elasticity. Alginate, κ-carrageenan, and low-methoxyl pectin can improve the adhesion and shear resistance of the gel through ionic crosslinking, thus achieving good retention even at lower dosages and reducing the risk of eye irritation or blurring caused by excessive use of a single gelling material. Amine polymers, such as aminated hyaluronic acid salts, chitosan and its derivatives, or gelatin derivatives, are selected, with their amine content controlled within a reasonable range. This facilitates the formation of a stable and reversible imine bond dynamic crosslinking network with aldehyde-modified polysaccharides, ensuring the gel retains structural recovery and sustained adhesion even under blink shearing and tear dilution conditions. Through the synergistic effect of the above material systems, a comprehensive balance between gel-forming behavior, mechanical properties and user comfort can be achieved in complex ocular surface environments, thereby further improving the stability and application adaptability of ocular gel formulations.

[0015] Preferably, the ophthalmic gel formulation further includes at least one of the following: The lubricating and moisturizing component is 0.05-0.30 wt%, wherein the lubricating and moisturizing component is sodium hyaluronate and / or potassium hyaluronate; The solubilizing component, 0.50–5.00 wt%, is hydroxypropyl-β-cyclodextrin; Drug nanodispersions, wherein the drug nanodispersions include one or more of nonionic surfactant vesicles, liposomes or drug nanocrystals, and their average particle size is 10 to 500 nm. Furthermore, the ophthalmic gel formulation does not contain benzalkonium chloride, chlorhexidine, or thimerosal-based antibacterial agents.

[0016] In the above technical solution, by introducing lubricating and moisturizing components, solubilizing components, and / or drug nanodispersions outside the basic gelling system, the functionality and applicability of ophthalmic gel formulations are further enhanced. The lubricating and moisturizing components, selected from sodium hyaluronate and / or potassium hyaluronate, can form a hydrophilic lubricating layer within the gel network, synergistically interacting with the ocular surface mucus layer. This improves the spreadability and lubrication of the formulation on the ocular surface, reduces foreign body sensation, and enhances medication comfort, while also helping to maintain the moisture state of the cornea and conjunctiva. The solubilizing component, hydroxypropyl-β-cyclodextrin, can improve the solubility stability of hydrophobic or poorly soluble active ingredients in the aqueous phase through inclusion complexation, reducing the risk of drug precipitation or crystallization, and achieving a more uniform distribution within the gel network, which is beneficial for obtaining stable and predictable release behavior.

[0017] The drug nanodispersions exist in the form of nonionic surfactant vesicles, liposomes, or drug nanocrystals, with their particle size controlled within an appropriate range. This allows the active ingredient to form a stable reservoir structure within the gel system, delaying drug diffusion and improving ocular surface absorption conditions without significantly affecting gelling behavior and rheological properties. Through the synergistic design of the above functional components and the in-situ gel system, lubrication, moisturizing, solubilization, and controlled-release effects can be achieved while ensuring the physical stability and ease of use of the formulation. Furthermore, the ocular gel formulation is free of benzalkonium chloride, chlorhexidine, or thimerosal-based antibacterial agents, which helps reduce the risk of irritation and potential damage to ocular surface tissues during long-term use, making the formulation more suitable for repeated or long-term use.

[0018] Secondly, the present invention also provides a method for preparing the ophthalmic gel formulation, comprising the following steps: S1. Prepare an aqueous solution of a temperature-sensitive gelling polymer to obtain a polymer phase solution; S2. Prepare an aqueous solution of ion-sensitive gelling polysaccharide to obtain a polysaccharide phase solution; S3. Prepare aldehyde-modified polysaccharide solution and amino polymer solution respectively; S4. Mix the aldehyde-modified polysaccharide solution with the amino polymer solution to obtain a dynamic crosslinking precursor solution; S5. Mix the dynamic crosslinking precursor solution with the polymer phase solution and the polysaccharide phase solution to obtain a mixture; S6. Add the buffer system components and isotonic regulator to the mixture and adjust the pH. Make up the volume to obtain the ophthalmic gel formulation.

[0019] Preferably, step S1 is carried out at 2-8°C, and the mixing temperature of step S5 is not higher than 15°C. In step S2, the ion-sensitive gelling polysaccharide is dissolved by heating and then cooled to below 25°C before proceeding to step S5. The buffer system components are selected from one or more of the following: a borate buffer system composed of boric acid and borax, a phosphate buffer system composed of sodium dihydrogen phosphate and disodium hydrogen phosphate, and a citrate buffer system composed of citric acid and sodium citrate; the isotonic regulator is selected from one or more of the following: sodium chloride, potassium chloride, mannitol, sorbitol, and glycerol. Furthermore, the filterable raw material solutions are sterilized by 0.22μm filtration and mixed and filled under aseptic conditions.

[0020] Thirdly, the present invention also provides a method for preparing an ophthalmic drug delivery packaging component, wherein the ophthalmic gel preparation is filled and sealed in an ophthalmic container under aseptic conditions to obtain an ophthalmic drug delivery packaging component. The ophthalmic container is either a single-dose sterile container or a multi-dose container equipped with an anti-backflow structure.

[0021] The ophthalmic gel formulation and its preparation method provided by this invention have at least the following beneficial effects: (1) The present invention constructs an in-situ gelling system by synergistically combining temperature-sensitive gelling polymers and ion-sensitive gelling polysaccharides, so that the ophthalmic gel formulation maintains good fluidity during the drop application stage and can quickly form a stable gel under temperature changes and tear ion action after entering the ocular surface environment, thereby effectively improving the retention ability of the formulation on the ocular surface and reducing the impact of tear dilution and blink shearing on the clearance of the formulation.

[0022] (2) By introducing an imine bond dynamic cross-linking network formed by aldehyde polysaccharide and amine polymer into the gelling system, the gel has a certain structural recovery ability when subjected to shearing, which is beneficial to maintain the gel morphology and mechanical stability in complex ocular surface environment, and to achieve a smooth and controllable release process of active ingredients, thereby improving the continuity and stability of medication.

[0023] (3) The ophthalmic gel formulation may be further introduced with lubricating and moisturizing components, solubilizing components and / or drug nanodispersions as needed, and may be used in combination with single-dose or multi-dose packaging with anti-reflux structure without adding benzalkonium chloride, chlorhexidine or thimerosal antibacterial agents. This helps to reduce the risk of antibacterial agent-related irritation while ensuring sterility and safety, and improve the tolerance of the formulation to ocular surface tissues and its suitability for long-term use. Attached Figure Description

[0024] Figure 1 Comparison of apparent viscosity of each embodiment and comparative example at 25°C; Figure 2 Comparison of in-situ gelation temperatures between various embodiments and comparative examples; Figure 3 Comparison of the recovery rates of the thixotropic structures in each embodiment and the comparative example; Figure 4 A comparison diagram of the adhesion and peel force of each embodiment and the comparative example; Figure 5 Comparison of cumulative drug release over 4 hours between each embodiment and the comparative example. Detailed Implementation

[0025] To better understand the above technical solutions, a detailed description of the solutions will be provided below in conjunction with the accompanying drawings and specific embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0026] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” as used in the embodiments of this invention and the appended claims are also intended to include the plural forms, and “multiple” generally includes at least two unless the context clearly indicates otherwise.

[0027] It should also be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that an article or device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such an article or device. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the article or device that includes said element.

[0028] This invention provides an ophthalmic gel formulation comprising, by weight percentage, the following raw materials: This invention provides an ophthalmic gel formulation, which comprises, by weight percentage, the following raw materials: (1) Temperature-sensitive gelling polymer, 13-26 wt%, wherein the temperature-sensitive gelling polymer is used to endow the formulation with the ability to undergo reversible sol-gel transition under different temperature conditions, so that the formulation maintains a low viscosity at room temperature or low temperature, making it easy to drop, and aggregates and forms a primary gel network after contacting the surface temperature of the eye.

[0029] The temperature-sensitive gelling polymer includes one or more of the following: polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer, and cellulose ethers that exhibit temperature-sensitive gelation behavior in an aqueous phase.

[0030] In a preferred embodiment, the temperature-sensitive gelling polymer includes poloxamer block copolymers and / or poloxamine block copolymers, such as poloxamer 407, and can be used in combination with poloxamer 188 to achieve a balance between gelling temperature, system viscosity and drip smoothness.

[0031] (2) Ion-sensitive gelling polysaccharide, 0.05-0.30 wt%, wherein the ion-sensitive gelling polysaccharide is used to form or enhance the gel network in the presence of sodium ions, potassium ions and / or calcium ions in tears, thereby making the primary gel more compact and improving adhesion and shear resistance.

[0032] The ion-sensitive gelling polysaccharide includes one or more of gellan gum, deacetylated gellan gum, alginate and its sodium or calcium salts, κ-carrageenan, and low-methoxyl pectin. In a preferred embodiment, gellan gum or deacetylated gellan gum can be used to obtain a gel system with high transparency and structural stability at a lower dosage.

[0033] (3) Aldehyde-modified polysaccharide, 0.02–0.20 wt%, wherein the aldehyde-modified polysaccharide provides aldehyde sites that can undergo condensation reactions with amino groups, enabling the formation of a dynamic covalent cross-linked network in the system. In a preferred embodiment, the aldehyde-modified polysaccharide includes one of aldehyde-modified gellan gum, oxidized dextran, or aldehyde-modified hyaluronic acid, and its aldehyde content is controlled within a suitable range to avoid excessive cross-linking that would lead to an overly rigid system.

[0034] (4) An amino polymer, 0.05–0.50 wt%, wherein the amino polymer and the aldehyde-modified polysaccharide form an imine bond crosslinking network through aldehyde and amino group condensation, enabling the gel to possess a certain structural recovery ability under shear. The amino polymer includes one or more of amino-modified sodium hyaluronate, amino-modified potassium hyaluronate, chitosan, quaternized chitosan, and gelatin derivatives, and its amino content is 0.05–2.00 mmol / g. In a preferred embodiment, an amino polymer of amino acid salts can be used to balance crosslinking ability and ocular biocompatibility.

[0035] (5) A buffer system component, 0.01–2.00 wt%, wherein the buffer system component is used to adjust the pH value of the ophthalmic gel formulation to make it closer to the physiological environment of the ocular surface, thereby reducing the risk of irritation and improving user comfort. In one embodiment, the buffer system component includes one or more of a borate buffer system, a phosphate buffer system, or a citrate buffer system.

[0036] (6) An isotonic regulator, 0.10–2.00 wt%, wherein the isotonic regulator is used to adjust the osmotic pressure of the formulation to match the tear environment. In one embodiment, the isotonic regulator comprises one or more of sodium chloride, potassium chloride, mannitol, sorbitol, or glycerol.

[0037] (7) A lubricating and moisturizing component, 0.05–0.30 wt%, wherein the lubricating and moisturizing component is used to improve the spreadability and lubricity of the gel on the ocular surface, reduce foreign body sensation, and maintain the moist state of the ocular surface. In a preferred embodiment, the lubricating and moisturizing component is sodium hyaluronate and / or potassium hyaluronate.

[0038] (8) Solubilizing component, 0.50 to 5.00 wt%, wherein the solubilizing component is used to improve the solubility stability of hydrophobic or poorly soluble active ingredients in the aqueous phase.

[0039] In a preferred embodiment, the solubilizing component is hydroxypropyl-β-cyclodextrin.

[0040] (9) A drug nanodispersion, wherein the drug nanodispersion is used as a dispersion and reservoir structure for an active ingredient to achieve sustained and stable release in a gel system. The drug nanodispersion comprises one or more of nonionic surfactant vesicles, liposomes, or drug nanocrystals, and has an average particle size of 10–500 nm.

[0041] In one embodiment, a drug nanodispersion can be prepared first, and then added to the above-mentioned gelling system and dispersed uniformly.

[0042] (10) The remainder is water.

[0043] In the above embodiments, the ophthalmic gel formulation does not contain benzalkonium chloride, chlorhexidine or thimerosal antibacterial agents, and can be used in conjunction with single-dose sterile containers or multi-dose containers with anti-backflow structures, thereby ensuring sterility and safety while reducing the risk of irritation associated with antibacterial agents. Example 1:

[0044] This embodiment provides an ophthalmic gel formulation, comprising, by weight percentage: 19.00 wt% temperature-sensitive gelling polymer, 0.15 wt% ion-sensitive gelling polysaccharide, 0.10 wt% aldehyde-modified polysaccharide, 0.15 wt% amino polymer, 0.50 wt% buffer system component, 0.80 wt% isotonic regulator, 0.15 wt% lubricating and moisturizing component, 2.00 wt% solubilizing component, 0.50 wt% drug nanodispersion (based on solids), and the balance being water.

[0045] The temperature-sensitive gelling polymer is composed of 16.00 wt% poloxamer 407 and 3.00 wt% poloxamer 188.

[0046] The ion-sensitive gelling polysaccharide is 0.15 wt% deacetylated gellan gum.

[0047] The aldehyde-modified polysaccharide is 0.10 wt% aldehyde-modified sodium hyaluronate.

[0048] The amine polymer is 0.15 wt% aminated sodium hyaluronate, with an amine content of 0.50 mmol / g.

[0049] The buffer system is composed of boric acid / borax buffer system, and the isotonic regulator is sodium chloride.

[0050] The lubricating and moisturizing component is sodium hyaluronate 0.15wt%, and the solubilizing component is hydroxypropyl-β-cyclodextrin 2.00wt%.

[0051] The drug nanodispersion is a nonionic surfactant vesicle with an average particle size of 200 nm.

[0052] The ophthalmic gel formulation of this embodiment does not contain benzalkonium chloride, chlorhexidine, or thimerosal-based antibacterial agents.

[0053] The preparation method of this embodiment is as follows: prepare an aqueous solution of poloxamer 407 / poloxamer 188 at 2-8℃ and let it stand at low temperature until it becomes clear to obtain a polymer phase solution.

[0054] After heating and dissolving deacetylated gellan gum, the solution was cooled to below 25°C to obtain a polysaccharide phase solution.

[0055] Aldehyde-modified sodium hyaluronate solution and amino-modified sodium hyaluronate solution were prepared separately and mixed to obtain a dynamic crosslinking precursor solution.

[0056] The dynamic cross-linking precursor solution was mixed with the polymer phase solution and the polysaccharide phase solution at a temperature not exceeding 15°C. Buffer system components and isotonic regulators were added, and the pH was adjusted. The mixture was then brought to a final volume to obtain an ophthalmic gel formulation.

[0057] The filterable raw material solutions were sterilized by 0.22μm filtration and then mixed and filled under aseptic conditions to obtain the finished formulation. Example 2:

[0058] The difference between this embodiment and Example 1 is that the total amount of temperature-sensitive gelling polymer is 13.00 wt%, of which poloxamer 407 is 12.00 wt%, poloxamer 188 is 1.00 wt%, and the amount of aldehyde-modified polysaccharide is 0.05 wt%; the rest is the same as in Example 1. Example 3:

[0059] The difference between this embodiment and Example 1 is that the total amount of the temperature-sensitive gelling polymer is 26.00 wt%, of which poloxamer 407 is 20.00 wt% and poloxamer 188 is 6.00 wt%; the rest is the same as in Example 1. Example 4:

[0060] The difference between this embodiment and Embodiment 1 is that the amount of ion-sensitive gelling polysaccharide (deacetylated gellan gum) used is 0.05 wt%; the rest is the same as in Embodiment 1. Example 5:

[0061] The difference between this embodiment and Embodiment 1 is that the ion-sensitive gelling polysaccharide is replaced with sodium alginate and the amount used is 0.30 wt%; the rest is the same as in Embodiment 1. Example 6:

[0062] The difference between this embodiment and Embodiment 1 is that the aldehyde polysaccharide is replaced with oxidized dextran and the amount is 0.02 wt%, and the amount of the lubricating and moisturizing component sodium hyaluronate is 0.05 wt%; the rest is the same as in Embodiment 1. Example 7:

[0063] The difference between this embodiment and Embodiment 1 is that: the amount of aldehyde-modified sodium hyaluronate is 0.20 wt%, the amount of amine polymer is 0.20 wt%, and the lubricating and moisturizing component is changed to potassium hyaluronate with an amount of 0.30 wt%; the rest is the same as in Embodiment 1. Example 8:

[0064] The difference between this embodiment and Example 1 is that the amount of amine polymer (aminated sodium hyaluronate) is 0.05 wt%, the amount of hydroxypropyl-β-cyclodextrin is 0.50 wt%, and no drug nanodispersion is added; the rest is the same as in Example 1. Example 9:

[0065] The difference between this embodiment and Example 1 is that: the amine polymer is replaced with quaternized chitosan at a dosage of 0.50 wt%, the aldehyde polysaccharide is replaced with oxidized dextran at a dosage of 0.10 wt%, the hydroxypropyl-β-cyclodextrin dosage is 5.00 wt%, and the drug nanodispersion is replaced with drug nanocrystals at an average particle size of 80 nm; the rest is the same as in Example 1. Example 10:

[0066] The difference between this embodiment and Example 1 is that: the temperature-sensitive gelling polymer is replaced with a poloxamine block copolymer at a dosage of 18.00 wt%; the ion-sensitive gelling polysaccharide is replaced with κ-carrageenan at a dosage of 0.15 wt%; the amine polymer is replaced with a gelatin derivative at a dosage of 0.20 wt%; and the drug nanodispersion is replaced with liposomes at an average particle size of 350 nm; the rest is the same as in Example 1.

[0067] Comparative Example 1

[0068] The difference between this comparative example and Example 1 is that: no ion-sensitive gelling polysaccharide, aldehyde polysaccharide and amino polymer are added, only poloxamer 4072 5.00wt% and poloxamer 1881 0.00wt% are used as the temperature-sensitive gelling polymer system, and the amount of hydroxypropyl-β-cyclodextrin is 5.00wt%; the rest is the same as in Example 1.

[0069] Comparative Example 2

[0070] The difference between this comparative example and Example 1 is that no aldehyde polysaccharide and amino polymer are added, and the temperature-sensitive gelling polymer and ion-sensitive gelling polysaccharide are respectively the poloxamer 407 / poloxamer 188 system and the deacetylated gelling gel system in Example 1; the rest is the same as in Example 1.

[0071] Comparative Example 3

[0072] The difference between this comparative example and Example 1 is that no temperature-sensitive gelling polymer, aldehyde polysaccharide, and amine polymer are added; only 0.30 wt% gellan gum is used as the ion-sensitive gelling polysaccharide system. The rest is the same as in Example 1.

[0073] The specific differences between Examples 1-10 and Comparative Examples 1-3 are shown in Table 1: Table 1 serial number Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Comparative Example 1 Comparative Example 2 Comparative Example 3 Thermosensitive gelling polymer (wt%) 19.00 13.00 26.00 19.00 19.00 19.00 19.00 19.00 19.00 18.00 35.00 19.00 0.00 Thermosensitive polymer type poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers poloxamer block copolymers Poloxamine block copolymers poloxamer block copolymers poloxamer block copolymers — P407 (wt%) 16.00 12.00 20.00 16.00 16.00 16.00 16.00 16.00 16.00 0.00 25.00 16.00 0.00 P188 (wt%) 3.00 1.00 6.00 3.00 3.00 3.00 3.00 3.00 3.00 0.00 10.00 3.00 0.00 Other thermosensitive polymers (wt%) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 18.00 0.00 0.00 0.00 Ion-sensitive gelling polysaccharide (wt%) 0.15 0.15 0.15 0.05 0.30 0.15 0.15 0.15 0.15 0.15 0.00 0.15 0.30 Ion-sensitive polysaccharide types Deacetylated gel Deacetylated gel Deacetylated gel Deacetylated gel Sodium alginate Deacetylated gel Deacetylated gel Deacetylated gel Deacetylated gel κ-carrageenan — Deacetylated gel Gel Aldehyde-modified polysaccharides (wt%) 0.10 0.05 0.10 0.10 0.10 0.02 0.20 0.10 0.10 0.10 0.00 0.00 0.00 Aldehyde-modified polysaccharide types Aldehyde-modified sodium hyaluronate Aldehyde-modified sodium hyaluronate Aldehyde-modified sodium hyaluronate Aldehyde-modified sodium hyaluronate Aldehyde-modified sodium hyaluronate Oxidized dextran (dialdehyde dextran) Aldehyde-modified sodium hyaluronate Aldehyde-modified sodium hyaluronate Oxidized dextran (dialdehyde dextran) Aldehyde-modified sodium hyaluronate — — — Amine polymers (wt%) 0.15 0.15 0.15 0.15 0.15 0.15 0.20 0.05 0.50 0.20 0.00 0.00 0.00 Amine polymer types Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Aminated sodium hyaluronate Quaternized chitosan Gelatin derivatives — — — Amine content (mmol / g) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 — — — — — Buffer system (wt%) 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Buffer system types boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system boric acid / borax buffer system Isotonic conditioner (wt%) 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 Types of isotonic regulators Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Sodium chloride Lubricating and moisturizing components (wt%) 0.15 0.15 0.15 0.15 0.15 0.05 0.30 0.15 0.15 0.15 0.00 0.15 0.00 Types of lubricating and moisturizing components Sodium hyaluronate Sodium hyaluronate Sodium hyaluronate Sodium hyaluronate Sodium hyaluronate Sodium hyaluronate Potassium hyaluronic acid Sodium hyaluronate Sodium hyaluronate Sodium hyaluronate — Sodium hyaluronate — Solubilizing component (wt%) 2.00 2.00 2.00 2.00 2.00 2.00 2.00 0.50 5.00 2.00 5.00 2.00 0.00 Types of solubilizing components Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin — Drug nanodispersions (wt%, solids) 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.00 0.50 0.50 0.00 0.50 0.00 Nanodispersion types Nonionic surfactant vesicles Nonionic surfactant vesicles Nonionic surfactant vesicles Nonionic surfactant vesicles Nonionic surfactant vesicles Nonionic surfactant vesicles Nonionic surfactant vesicles — Drug nanocrystals Liposomes — Nonionic surfactant vesicles — Average particle size (nm) 200 200 200 200 200 200 200 — 80 350 — 200 — Test methods To verify the flowability, in-situ gelling ability after entering the ocular surface, structural recovery ability under blink shear, adhesion and retention ability on the ocular surface, and controllability of drug release of the ocular gel formulation of the present invention during the drop application stage, the following key parameters and test methods can be set. Unless otherwise specified, each test can be performed at least three times in parallel and the average value is taken; at the same time, a control sample can be set to highlight the difference in the synergistic effect of the "temperature-sensitive gelling system + ion-sensitive gelling system + aldehyde-based polysaccharide-amine polymer dynamic crosslinking network" of the present invention.

[0074] 1) Evaluation of dripping viscosity and dripability The test formulation was used as a sample, and its apparent viscosity was measured under the preparation and storage conditions to characterize its flowability and addability during the drop application stage. The test can be performed using a rotational viscometer or rheometer, and the viscosity value after the reading stabilizes under isothermal conditions. The testing process followed the general requirements for viscosity measurement in the national standard GB / T10247-2008, including temperature control and reading interpretation. For temperature-sensitive systems, tests could be conducted at room temperature and near ocular surface temperature to compare the effect of temperature increase on drop viscosity.

[0075] 2) Evaluation of simulated tear-triggered in-situ thickening / gelation behavior Samples were mixed with artificial tears at a preset ratio, and the sol-to-gel transition, viscosity changes, or flowability changes were observed under conditions close to ocular surface temperature to characterize the triggering effect of the ionic environment on ion-sensitive gelling polysaccharides and their synergistic thickening effect with temperature-sensitive gelling polymers. Evaluation methods included (i) viscosity changes after mixing (viscosity was measured before and after mixing); (ii) inverted non-flowing method / flowing distance method (whether significant flow or flow distance occurred within the same time window); and (iii) rheological temperature scanning and comparison with the ionic environment (see item 3 below).

[0076] 3) Evaluation of gelation temperature and gelation time To quantify the in-situ gelation window, gelation temperature and gelation time can be measured on the sample. The gelation temperature can be determined using linear oscillatory shear rheology testing. Temperature scans are used to record the curves of storage modulus G' and loss modulus G'' as a function of temperature, and the temperature at which G' first exceeds G'' is taken as the gelation temperature. The gelation time can be determined using the stirring retardation method under isothermal conditions: the sample is placed in a constant-temperature water bath and stirred at a constant speed; the time it takes for the stir bar to stop rotating or for stable retardation to occur is recorded as the gelation time.

[0077] 4) Evaluation of structural recovery ability against blink shear To characterize the reversible fracture and recovery ability of dynamically cross-linked networks under shear stress, cyclic shear or three-stage shear tests can be used to evaluate the structural recovery of samples. The test procedure is as follows: Initial viscosity or modulus is recorded as a baseline under low shear conditions; then high shear is applied to simulate blink shear failure; finally, the condition is restored to low shear conditions, and the recovery curves of viscosity or modulus over time are recorded. The recovery rate and the degree of recovery (the proportion of recovered value relative to the baseline) are used as evaluation indicators.

[0078] 5) Evaluation of adhesion and retention capabilities To quantitatively evaluate the macroscopic adhesion ability of the gel to the contact matrix, the "post-gelation peel adhesion" test can be used. The sample is placed in a specified container and brought into critical contact with the contact matrix (e.g., plexiglass, polytetrafluoroethylene, or other alternative simulated matrix). After gelation is completed under set conditions, the contact matrix is ​​moved vertically and uniformly upward at a constant speed using a texture analyzer or tensile testing device. The force-displacement curve generated during the peeling process is recorded, and the adhesion strength is characterized by the maximum peel force or the integral value of the curve.

[0079] 6) Evaluation of controllability of in vitro drug release To evaluate the sustained-release and controlled-release capabilities of the gel system of this invention for the active ingredient, in vitro release tests can be conducted using the dialysis bag method or a diffusion model. Taking the dialysis bag method as an example: a certain volume of sample is placed in a dialysis bag and sealed. The dialysis bag is then placed in a release medium under constant temperature conditions (the release medium can be artificial tears or a buffer system), and release is carried out under constant-speed oscillation conditions. Samples are taken at set time points, and an equal volume of fresh release medium is added to maintain sedimentation conditions. The concentration of the active ingredient in the sample at each time point is determined using high-performance liquid chromatography or ultraviolet spectrophotometry, and the cumulative release curve is calculated.

[0080] Test Results To evaluate the performance of the ophthalmic gel formulation of the present invention in key performance indicators such as drop flowability, in-situ gelation triggering, post-shear structural recovery, ocular surface adhesion and retention, and drug release control, systematic comparative tests were conducted on Examples 1-10 and Comparative Examples 1-3 according to the designed experimental scheme. The results are shown in Table 2: Table 2 Apparent viscosity at 25℃ (mPa·s) Gel forming temperature (°C) Thixotropic recovery rate (%) Adhesion peel force (mN) 4h cumulative release (%) Example 1 55 32.0 85 15 40 Example 2 45 31.5 83 14 42 Example 3 85 33.0 87 16 38 Example 4 52 32.0 84 13 41 Example 5 60 32.0 85 15 39 Example 6 50 31.8 82 12 43 Example 7 70 33.0 88 16 37 Example 8 48 32.0 80 14 44 Example 9 78 33.5 86 15 36 Example 10 62 32.5 85 15 39 Comparative Example 1 180 28.0 55 9 58 Comparative Example 2 58 32.0 70 12 48 Comparative Example 3 18 NA 65 10 55 (a) Drip fluidity like Figure 1 As shown, the apparent viscosity of each embodiment at 25°C is at a low to medium level (45-85 mPa·s), indicating that the temperature-sensitive gelling polymer and ion-sensitive polysaccharide ratio designed in this invention will not gel prematurely under room temperature conditions and has good dripping properties. Among them, the combination of low-temperature sensitive polymer and low-solubilizing component in Examples 2 and 8 is more conducive to further reducing dripping viscosity and improving dripping smoothness.

[0081] In contrast, the viscosity of Comparative Example 1 (a typical high-concentration poloxamer system) was much higher than that of the Example, reaching over 180 mPa·s. This indicates that relying solely on high-concentration temperature-sensitive polymers for gelation in the prior art significantly increases the viscosity of eye drops, which is detrimental to the experience of eye drop application and smooth drug delivery.

[0082] Comparative Example 3 (ion-sensitive single system) has too low a viscosity, only 18 mPa·s, and cannot form a sufficient in-situ gel network, indicating that although the single ion-sensitive polysaccharide system has good flowability during the dripping stage, its subsequent retention is significantly insufficient.

[0083] (ii) In-situ gelation triggering effect (gelation temperature / gelation temperature) like Figure 2 As shown, the gelation temperature range of the embodiments of the present invention all falls within about 31.5℃ to 33.5℃, which is very close to or slightly lower than the normal ocular surface temperature (about 32-34℃). This indicates that after being added in the tear film environment, it can quickly change from a sol to a gel state, which is beneficial to improving the residence time on the ocular surface.

[0084] The gelation temperature of Comparative Example 1 was 28.0℃, which was significantly low and may have led to premature gelation or discomfort before the blink of an eye. Comparative Example 3 did not include a temperature-sensitive gelation material, so no clear gelation crossover point (NA) could be observed in the temperature scan, indicating that reliable in-situ gelation could not be achieved through the temperature triggering mechanism.

[0085] Although Comparative Example 2 was designed with both temperature-sensitive and ion-sensitive responses, it lacked dynamic cross-linking network support, resulting in large fluctuations in gelation temperature and unstable gel reinforcement only under high shear / large disturbance conditions.

[0086] (iii) Structural recovery capacity after shearing like Figure 3 As shown, the shear recovery rates of the systems in the examples are all above approximately 80%, with some examples (e.g., Examples 3, 7, and 9) exhibiting even higher recovery rates of 86-89%. This indicates that the dynamic imine bond crosslinking network formed by the aldehyde-based polysaccharide and the amine polymer introduced in this invention can significantly recover its spatial network structure after the structure is sheared (e.g., shearing during blinking), thereby enhancing the gel's long-term retention ability.

[0087] In comparison, the recovery rate of Comparative Example 1 was only about 55%, Comparative Example 2 about 70%, and Comparative Example 3 about 65%. Comparative Example 1, being only a high-concentration thermosensitive gel, had a weak overall network structure recovery ability under shear. Comparative Example 2 lacked dynamic cross-linked network support, and although it had thermosensitive and ion-assisted recovery, its shear recovery was still not ideal. Comparative Example 3, although having a certain ion-sensitive gelling ability, lacked thermosensitive and dynamic cross-linking, and relied solely on a weak cross-linked structure, resulting in poor recovery ability.

[0088] (iv) Adhesion / retention potential

[0089] like Figure 4 As shown in the data, the adhesion-peeling force of the embodiments of the present invention, through the concentration design and multi-network structure synergistic design, resulted in peeling forces in the relatively high range of 12-17 mN, significantly higher than the 9 mN of Comparative Example 1, the 12 mN of Comparative Example 2, and the 10 mN of Comparative Example 3. In particular, Examples 3, 7, and 9 exhibited high adhesion forces, indicating that the gel of the present invention adheres more firmly to the simulated mucosal surface, thereby increasing the residence time on the ocular surface.

[0090] Compared with existing technologies, this invention enhances the adhesion properties of gels through the synergistic effect of a triple network of temperature-sensitive, ion-sensitive, and dynamic cross-linking, thereby achieving better retention potential without depending on the concentration of the high-temperature-sensitive polymer. This is the key manifestation of this invention's breakthrough over the limitations of existing technologies.

[0091] (v) Controllability of in vitro drug release like Figure 5As shown, the cumulative drug release over 4 hours in each embodiment exhibits moderate sustained-release characteristics, generally ranging from 36% to 44%, demonstrating a certain degree of drug release control. In particular, the drug release curves of Examples 1, 5, and 10 are flatter, showing a more stable drug release trend compared to similar single-mechanism formulations.

[0092] Comparative Example 1 is a thermosensitive monoclonal system, which releases approximately 58% in 4 hours. The rapid release may result in a short-lived and unsustainable peak of therapeutic effect. Comparative Example 2 is a monoclonal system without dynamic cross-linking, which releases approximately 48%, showing some sustained-release properties but is not as stable as the embodiments of the present invention. Comparative Example 3 is an ion-sensitive monoclonal system, which releases close to 55% without thermosensitivity and dynamic cross-linking mechanisms, indicating that its performance in controlled release is limited.

[0093] In this embodiment of the invention, the synergistic effect of temperature / ion sensitivity and dynamic cross-linking network enables the drug to be retained in the gel network to a greater extent, thereby achieving a more stable and controllable in vitro drug release curve.

[0094] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention. Clearly, those skilled in the art can make various alterations and modifications to the invention without departing from its spirit and scope. Thus, if these modifications and modifications of the invention fall within the scope of the claims and their equivalents, the invention is also intended to include these modifications and modifications.

Claims

1. An ophthalmic gel formulation, characterized in that, The ophthalmic gel formulation comprises the following raw materials by weight percentage: Temperature-sensitive gelling polymers: 13–26 wt% Ion-sensitive gelling polysaccharide 0.05–0.30 wt%; Aldehyde-modified polysaccharides: 0.02–0.20 wt%; Amine polymer 0.05–0.50 wt%; The buffer system components range from 0.01 to 2.00 wt%. Isotonic conditioner 0.10–2.00 wt%; The remainder is water; The aldehyde-modified polysaccharide and the amino polymer form an imine bond crosslinking network through the condensation of aldehyde and amino groups; the ophthalmic gel formulation is obtained by mixing and dissolving the raw materials and adjusting the pH.

2. The ophthalmic gel formulation as described in claim 1, characterized in that, The temperature-sensitive gelling polymer includes one or more of the following: polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer, and cellulose ethers that exhibit temperature-sensitive gelation behavior in an aqueous phase.

3. The ophthalmic gel formulation as described in claim 2, characterized in that, The temperature-sensitive gelling polymers include poloxamer block copolymers and / or poloxamine block copolymers; The poloxamer block copolymers include one or more of poloxamer 407, poloxamer 188, poloxamer 338, and poloxamer 403; The poloxamine block copolymers include polyoxyethylene-polyoxypropylene-ethylenediamine block copolymers with temperature-sensitive gelation behavior.

4. The ophthalmic gel formulation according to any one of claims 1 to 3, characterized in that, The ion-sensitive gelling polysaccharide includes anionic polysaccharides that can form or enhance a gel network in the presence of sodium, potassium and / or calcium ions, and the anionic polysaccharide includes one or more of gellan gum, deacetylated gellan gum, alginate and its sodium or calcium salts, K-carrageenan, and low-methoxyl pectin.

5. The ophthalmic gel formulation according to any one of claims 1 to 3, characterized in that, The aldehyde-modified polysaccharide includes one or more of aldehyde-modified gellan gum, oxidized dextran, aldehyde-modified sodium hyaluronate, and aldehyde-modified potassium hyaluronate; the aldehyde content of the aldehyde-modified polysaccharide is 0.05–2.00 mmol / g.

6. The ophthalmic gel formulation according to any one of claims 1 to 3, characterized in that, The amine polymer includes one or more of the following: aminated sodium hyaluronate, aminated potassium hyaluronate, chitosan, quaternized chitosan, and gelatin derivatives; the amine content of the amine polymer is 0.05–2.00 mmol / g.

7. The ophthalmic gel formulation according to any one of claims 1 to 3, characterized in that, The ophthalmic gel formulation further includes at least one of the following: The lubricating and moisturizing component is 0.05-0.30 wt%, wherein the lubricating and moisturizing component is sodium hyaluronate and / or potassium hyaluronate; The solubilizing component, 0.50–5.00 wt%, is hydroxypropyl-β-cyclodextrin; the drug nanodispersion comprises one or more of nonionic surfactant vesicles, liposomes, or drug nanocrystals, and has an average particle size of 10–500 nm; and the ophthalmic gel formulation is free of benzalkonium chloride, chlorhexidine, or thimerosal-based antibacterial agents.

8. A method for preparing an ophthalmic gel formulation as described in any one of claims 1 to 7, characterized in that, Includes the following steps: S1. Prepare an aqueous solution of a temperature-sensitive gelling polymer to obtain a polymer phase solution; S2. Prepare an aqueous solution of ion-sensitive gelling polysaccharide to obtain a polysaccharide phase solution; S3. Prepare aldehyde-modified polysaccharide solution and amino polymer solution respectively; S4. Mix the aldehyde-modified polysaccharide solution with the amino polymer solution to obtain a dynamic crosslinking precursor solution; S5. Mix the dynamic crosslinking precursor solution with the polymer phase solution and the polysaccharide phase solution to obtain a mixture; S6. Add the buffer system components and isotonic regulator to the mixture and adjust the pH. Make up the volume to obtain the ophthalmic gel formulation.

9. The preparation method according to claim 8, characterized in that: Step S1 is carried out at 2-8℃, and the mixing temperature of step S5 is not higher than 15℃. In step S2, the ion-sensitive gelling polysaccharide is dissolved by heating and then cooled to below 25°C before proceeding to step S5. The buffer system components are selected from one or more of the following: a borate buffer system composed of boric acid and borax, a phosphate buffer system composed of sodium dihydrogen phosphate and disodium hydrogen phosphate, and a citrate buffer system composed of citric acid and sodium citrate; the isotonic adjuster is selected from one or more of sodium chloride, potassium chloride, mannitol, sorbitol, and glycerol; and the filterable raw material solutions are sterilized by 0.22 μm filtration and mixed and filled under aseptic conditions.

10. A method for preparing an ophthalmic drug delivery packaging component, characterized in that, The ophthalmic gel formulation as described in any one of claims 1 to 7 is aseptically filled and sealed in an ophthalmic container to obtain an ophthalmic drug delivery packaging assembly. The ophthalmic container is either a single-dose sterile container or a multi-dose container equipped with an anti-backflow structure.

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