PEG-PLGA (polyethylene glycol-poly (lactic-co-glycolic acid)) temperature-sensitive tear suppository and application thereof in preparation of xerophthalmia medicine

Abstract

The invention relates to a PEG-PLGA (polyethylene glycol-poly (lactic-co-glycolic acid)) temperature-sensitive tear suppository and application thereof in preparation of a medicine for treating xerophthalmia, and belongs to the technical field of biological materials. The PEG-PLGA temperature-sensitive tear suppository disclosed by the invention is formed by carrying out temperature-sensitive phase change on eye drops prepared from a PEG-PLGA high polymer material; after the eye drops flow into the lacrimal punctum, a gel-shaped lacrimal suppository is formed in situ according to the physiological morphology of the lacrimal punctum. The PEG-PLGA temperature-sensitive tear suppository has a solution-gel-solution reversible temperature-sensitive characteristic, can form a tear suppository in a lacrimal punctum or dissolve into a solution according to temperature change, and is more flexible and convenient to use. And the preparation method is simple and feasible, is suitable for large-scale production, and can meet clinical requirements.

Description

Technical Field

[0001] This invention relates to the field of biomaterials technology, specifically to a PEG-PLGA thermosensitive tear plug and its application in the preparation of drugs for dry eye syndrome. Background Technology

[0002] Dry eye syndrome is a chronic ocular surface disease that seriously affects quality of life. Its pathogenesis is complex, involving multiple factors such as inflammatory responses and abnormal tear dynamics. In my country, the prevalence of dry eye syndrome has reached 21%-30%, making it the second most common ophthalmic disease after myopia. Initially, patients often experience discomfort such as dryness, a foreign body sensation, and eye strain. As the condition progresses, significant burning sensations, redness, pain, and photophobia may appear. In severe cases, complications such as corneal epithelial defects and ulcers may occur, causing substantial damage to visual function.

[0003] Currently, clinical treatment still relies on eye drops such as artificial tears as the basic treatment plan, but these traditional treatment methods have significant limitations. Because the medication has a short residence time on the ocular surface, patients need to use them frequently, severely impacting treatment adherence. More importantly, this symptomatic treatment cannot fundamentally improve pathological changes such as insufficient tear secretion or excessive evaporation, and its effectiveness is particularly limited for moderate to severe cases. Addressing these treatment bottlenecks, the 2017 Dry Eye Symposium II (DEWS II) guidelines of the Tear Film and Ocular Surface Society explicitly listed lacrimal duct occlusion as an important treatment option for dry eye. Lacrimal duct occlusion involves implanting a specially designed plug to block the tear drainage channel; this innovative treatment concept is similar to the physical principle of "blocking a drainpipe." In terms of treatment mechanism, by reducing tear loss, it significantly prolongs the residence time of autologous tears and medications on the ocular surface, effectively relieving symptoms and significantly reducing the frequency of artificial tear use. Based on clinical needs, existing lacrimal duct plugs are mainly divided into two categories: permanent and absorbable. The former uses inert materials such as silicone and is suitable for chronic patients requiring long-term treatment; the latter uses biodegradable biomaterials such as collagen and is mainly used for treatment evaluation and short-term intervention. The development of an ideal lacrimal duct plug needs to consider multiple performance requirements. In terms of material properties, it must possess excellent biocompatibility and appropriate mechanical strength; in terms of product design, it needs to precisely match the lacrimal duct anatomy; and in terms of functionality, it must ensure stable therapeutic effects while facilitating clinical monitoring.

[0004] However, clinical practice shows that lacrimal duct embolization is not without risks. The most common complication is embolus displacement, including complete detachment or partial expulsion, with an incidence rate as high as 10%. In addition, varying degrees of local inflammation may occur during treatment, and in severe cases, it may develop into infectious canaliculitis. Long-term implantation may also induce granulation tissue hyperplasia, while improper operation may lead to mechanical damage to the lacrimal duct. A small number of patients may experience paradoxical epiphora or allergic reactions to the implant material, and in very rare cases, even a temporary worsening of symptoms may occur.

[0005] Currently, lacrimal duct embolization therapy is in a phase of rapid development. The research and development of new materials, the realization of personalized designs, and advancements in minimally invasive implantation techniques are continuously improving the safety and effectiveness of this treatment. In the future, with the development of bioengineering technology, the application of innovative technologies such as intelligent responsive materials and drug sustained-release systems is expected to bring revolutionary breakthroughs to the treatment of dry eye syndrome. This will not only significantly improve the treatment level of ocular surface diseases but also provide more patients with better treatment options. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a PEG-PLGA thermosensitive tear plug and its application in the preparation of drugs for dry eye syndrome. The PEG-PLGA thermosensitive tear plug of this invention is formed from eye drops prepared from PEG-PLGA polymer material through a thermosensitive phase transition; after the eye drops flow into the lacrimal punctum, a gel-like tear plug forms in situ according to the physiological morphology of the lacrimal punctum. The PEG-PLGA thermosensitive tear plug of this invention possesses reversible thermosensitive properties of solution-gel-solution, capable of forming a tear plug or dissolving into a solution in the lacrimal punctum according to temperature changes, making it more flexible and convenient to use. Furthermore, the preparation method is simple and easy to implement, suitable for large-scale production, and can meet clinical needs.

[0007] This invention is achieved through the following technical solution:

[0008] The first objective of this invention is to provide a PEG-PLGA thermosensitive tear plug, which is formed by a thermosensitive phase transition of eye drops prepared from PEG-PLGA polymer material; after the eye drops flow into the lacrimal punctum, a gel-like tear plug is formed in situ according to the physiological morphology of the lacrimal punctum, blocking the lacrimal duct, and through its thermosensitive properties, it has the reversibility of solution-gel-solution.

[0009] In one embodiment of the present invention, the number-average molecular weight of the PEG-PLGA thermosensitive polymer material is 750-1870, which is relatively small and has low eye irritation.

[0010] In one embodiment of the present invention, the molar ratio of PEG to PLGA in the PEG-PLGA thermosensitive polymer material is 1:4-1:8.

[0011] In one embodiment of the present invention, the concentration of PEG-PLGA thermosensitive polymer material in the eye drops is 25 wt% or more.

[0012] In one embodiment of the present invention, the pH value of the eye drops is 6.5-7.5.

[0013] In one embodiment of the present invention, the gelation temperature of the eye drops is greater than or equal to 37°C, and the gelation time is 1-2 seconds.

[0014] In one embodiment of the present invention, the PEG-PLGA thermosensitive tear plug forms a solution at a temperature of 30°C or less for 1-2 seconds.

[0015] In one embodiment of the present invention, the eye drops are obtained by dissolving PEG-PLGA polymer material in physiological saline, followed by sterilization and stirring.

[0016] In one embodiment of the present invention, the PEG-PLGA polymer material is dissolved in physiological saline and stirred for 12 hours under sterilization conditions of 4 degrees Celsius and ultraviolet light to finally prepare eye drops. The stirring speed is 50-500 RPM to ensure that the PEG-PLGA polymer material is fully dissolved in physiological saline.

[0017] In one embodiment of the present invention, the PEG-PLGA polymer further includes drug-loading properties.

[0018] In one embodiment of the present invention, the eye drops further include a small molecule water-soluble drug, a small molecule lipid-soluble drug, and a large molecule bioactive drug; the small molecule water-soluble drug includes diquafosol sodium; the small molecule lipid-soluble drug includes cyclosporine A and tacrolimus; and the large molecule bioactive drug includes human epidermal growth factor and fibroblast growth factor.

[0019] A second objective of this invention is to provide the application of the aforementioned PEG-PLGA thermosensitive tear plug in the preparation of a drug for treating dry eye syndrome.

[0020] The PEG-PLGA thermosensitive tear plug of this invention is a gel formed in situ by PEG-PLGA polymer eye drops flowing into the lacrimal punctum, based on the physiological morphology of the lacrimal punctum, without a fixed shape or length. The gelation temperature of this tear plug is above 37 degrees Celsius, which can precisely limit the gelation area within the lacrimal canaliculi, thereby effectively avoiding the risk of premature gelation on the ocular surface and diffusion to surrounding tissues such as the lacrimal sac.

[0021] The technical solution of the present invention has the following advantages compared with the prior art:

[0022] (1) This invention provides a PEG-PLGA thermosensitive tear plug and its application in the preparation of dry eye drugs. The PEG-PLGA thermosensitive polymer material can gel in situ at the lacrimal punctum, prolonging the residence time of tears on the ocular surface by blocking the lacrimal duct, thereby relieving dry eye symptoms. This material has sensitive temperature response and can complete the "solution → gel" phase transition process within 2 seconds, with a gelation rate significantly better than existing thermosensitive gel materials. Its thermosensitive characteristics originate from the synergistic effect of hydrophilic and hydrophobic segments of the polymer chain. At 25°C, the material is dispersed in the form of core-shell spherical micelles, where PLGA constitutes the hydrophobic core and PEG forms the hydrophilic shell; when the temperature rises to 37°C, the aggregation tendency of the hydrophobic PLGA core is significantly enhanced, which is sufficient to overcome the intermolecular hydration repulsion force, thereby forming continuously cross-linked hydrophobic microdomains, while the hydrophilic PEG segments maintain good water compatibility and act as hydrophilic spacers to stabilize the three-dimensional network structure. In short, when the ambient temperature reaches the phase transition threshold, the hydrophobic interaction and chain entanglement effect between polymer molecular chains are enhanced simultaneously, driving the system to rapidly transform from a fluid dynamic solution to a gel state.

[0023] (2) The tear plug has the reversibility of solution-gel-solution, and can be formed or dissolved in the tear punctum according to temperature changes, making it more flexible and convenient to use.

[0024] (3) PEG-PLGA polymer materials have good drug loading capacity and can encapsulate a variety of bioactive drugs, providing more possibilities for the treatment of dry eye syndrome.

[0025] (4) PEG-PLGA polymer materials have good biocompatibility and will not cause adverse eye reactions, making them safer and more reliable to use.

[0026] (5) The PEG-PLGA polymer material formulation has the dual functions of eye drops and tear plugs, requiring only one administration every two days, effectively solving the problem of frequent use required by traditional eye drops, while avoiding the problem of tear plug morphology mismatch caused by individual differences in lacrimal gland anatomy. The formulation has excellent safety, with no local inflammatory reaction or risk of plug displacement; and the gelation temperature is higher than 37℃, precisely matching the physiological temperature requirements of the lacrimal canaliculi, fundamentally avoiding the drawback of premature gelation of the material on the ocular surface, ensuring that the gelation range is strictly limited to the lacrimal canaliculi and will not spread to the lacrimal sac and other surrounding tissues.

[0027] (6) The preparation method of the present invention is simple and easy to implement, suitable for large-scale production, and can meet the needs of clinical practice.

[0028] In summary, the PEG-PLGA thermosensitive tear plug and its preparation method of the present invention have significant innovation and practicality, providing a new option for the treatment of dry eye syndrome. Attached Figure Description

[0029] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings.

[0030] Figure 1 This is a schematic diagram of the thermosensitive hydrogel tear plug designed in this invention for treating dry eye syndrome;

[0031] Figure 2 The following are the results of in vitro property verification of this invention: Figure a shows that the solution-gel-precipitation transition of the mPEG-PLGA thermogel is controlled by concentration and temperature; Figure b shows the hydrodynamic size and stability of the mPEG-PLGA micelles measured using a Zeta potentiometer; Figure c shows the rheological behavior of the thermogel as a function of temperature measured using a rheometer; Figure d shows the lacrimal duct occlusion capacity of the mPEG-PLGA thermogel; Figure e shows the reversibility verification of the mPEG-PLGA thermogel.

[0032] Figure 3 This invention verifies the gelation performance of mPEG-PLGA gel at 37 °C. Figure a shows the macroscopic observation of the temperature-sensitive solution-gel transition phenomenon, Figure b shows the microscopic morphology of the hydrogel as shown by transmission electron microscopy (TEM), and Figure c is a schematic diagram of the solution-gel transition mechanism.

[0033] Figure 4 This is a safety verification of the present invention. Figure a is a wide beam illumination image, Figure b is a fluorescein staining image, Figure c is a tear secretion image, and Figure d is an optical coherence tomography (OCT) image.

[0034] Figure 5 The figures show the corneal transparency and corneal damage degree of mice after different treatments according to the present invention. Figure a shows the corneal transparency and Figure b shows the corneal damage degree.

[0035] Figure 6 Figure 1 shows the degree of tear secretion in mice after different treatments according to the present invention. Figure 2a is a picture of actual tear secretion, and Figure 3b is the corresponding statistical chart.

[0036] Figure 7 These are microscopic images of mouse eyeballs after different treatments according to the present invention. Figure a is an optical coherence tomography (OCT) image, Figure b is a representative image of corneal hematoxylin-eosin (H&E) staining, and Figure c is a representative image of conjunctival periodate-Schiff (PAS) staining.

[0037] Figure 8 The figures show the corneal transparency and corneal damage degree of New Zealand rabbits after different treatments according to the present invention. Figure a shows the corneal transparency, Figure b shows the corneal damage degree, and Figure c shows the corresponding statistical chart.

[0038] Figure 9Figure 1 shows the degree of tear secretion in New Zealand rabbits after different treatments according to the present invention. Figure 2a is a picture of actual tear secretion, and Figure 3b is the corresponding statistical chart. Detailed Implementation

[0039] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0040] Existing triblock materials suffer from drawbacks such as low gelation temperatures (generally below 37°C) and excessively large molecular weights. Effective gelation within the lacrimal canaliculi requires a temperature threshold above 37°C, causing the materials to gel prematurely on the ocular surface before flowing into the lacrimal punctum, failing to form a therapeutic lacrimal plug within the lacrimal duct. In contrast, the biblock mPEG-PLGA material of this invention has a precisely controlled molecular weight of 750-1870 and a stable gelation temperature above 37°C, precisely matching the physiological temperature requirements of the lacrimal canaliculi, preventing premature gelation on the ocular surface, and ensuring the in-situ formation of an effective lacrimal plug within the lacrimal duct. Furthermore, larger molecular weights generally result in greater ocular irritation; the biblock mPEG-PLGA material of this invention has a smaller molecular weight, resulting in less ocular irritation and significantly improved stability of gelation concentration under physiological conditions, further ensuring the safety and reliability of clinical applications.

[0041] Compared with existing similar materials, which can only achieve a one-way transformation from "solution to gel", the tear plug hydrogel material for dry eye treatment of the present invention has a unique reversible transformation property of "solution → gel → resolution", which improves the flexibility and safety of drug use and fills the gap in reversible temperature-sensitive regulation of existing materials.

[0042] The first aspect of this invention provides a method for preparing PEG-PLGA thermosensitive gel, and demonstrates that PEG-PLGA solution gradually self-assembles from a polymer solution state into nanoparticles as the temperature increases, eventually forming a hydrogel state.

[0043] This invention demonstrates the gelation temperatures of PEG-PLGA at different concentrations, clarifying the concentration range exhibiting gelation properties at the lacrimal punctum temperature. To improve its biocompatibility, the animal experiments in the specific embodiments all used a concentration of 25 wt%, and employed a 45°C heat pack to assist gelation.

[0044] Furthermore, it was demonstrated that the PEG-PLGA solution maintains a stable nanoparticle form under low-temperature storage conditions, exhibiting good stability.

[0045] Furthermore, the ability of PEG-PLGA as a thermosensitive tear plug to occlude the lacrimal puncta in New Zealand rabbits was demonstrated, with the administration frequency clearly defined as once every two days.

[0046] The second aspect of this invention demonstrates the biocompatibility and low ocular irritation of PEG-PLGA thermosensitive tear plugs, including corneal and conjunctival tissue safety and tear secretion status.

[0047] The third aspect of this invention utilizes the PEG-PLGA thermosensitive tear plug provided in the first aspect and a defined drug delivery strategy to demonstrate the therapeutic effect of the thermosensitive tear plug on dry eye syndrome.

[0048] Furthermore, in mice, thermosensitive tear plugs demonstrated better treatment efficacy for dry eye compared to commercially available sodium hyaluronate.

[0049] Furthermore, in New Zealand rabbits, thermosensitive tear plugs demonstrated superior drug delivery and better treatment efficacy for dry eye compared to commercially available silicone tear plugs.

[0050] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used are commercially available.

[0051] PEG-PLGA was purchased from Xi'an Qiyue Biotechnology Co., Ltd. Mice were purchased from Changzhou Cavens Laboratory Animal Co., Ltd. Animal experiments were conducted in accordance with the approval of the Animal Ethics Committee of Soochow University.

[0052] Example 1: Preparation of a PEG-PLGA-based thermosensitive tear plug

[0053] Different masses of PEG-PLGA were weighed, with a number-average molecular weight of 750-1870 and a LA to GA molar ratio of 6:1 in the synthesis of PLGA. PEG-PLGA was dissolved in physiological saline to prepare a series of concentrations, including 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, and 40 wt%. Each solution was placed in a water bath controlled by a temperature controller, and the transition from solution to gel was recorded, and a phase transition diagram was plotted. Figure 2 As shown in Figure a, PEG-PLGA solutions of different concentrations have different critical phase transition temperatures. This invention uses a lacrimal duct temperature of 35 degrees Celsius as the standard and selects concentration ranges at or below 35 degrees Celsius that can form gels, i.e., concentrations above 25 wt%, which are considered to be effective gel-forming ranges for thermosensitive lacrimal plugs and maintain embolism at body temperature.

[0054] Next, 25 wt% PEG-PLGA was selected for physical property characterization. PEG-PLGA was dissolved in physiological saline and stirred at 50 RPM for 12 hours at 4°C to obtain a PEG-PLGA micelle solution. The instantaneous particle size and polydispersity index (PDI) were then measured using a particle size analyzer at 0, 4, 8, 12, 24, and 48 hours. The results are shown below. Figure 2 As shown in b, PEG-PLGA micelles are relatively stable in physiological saline, which is beneficial for storage.

[0055] Next, the modulus change of 25 wt% PEG-PLGA micelles under continuously increasing temperature was observed using a rotational rheometer. Figure 2 As shown in c, the modulus of PEG-PLGA micelles at this concentration changed dramatically when the temperature rose to 35 degrees Celsius, indicating a transformation from solution to gel. To test whether this hydrogel could act as a tear plug and reduce tear loss, a tear duct occlusion test was conducted using New Zealand rabbits. PEG-PLGA eye drops (10 μL) were applied to the left eye of three rabbits, and a 45-degree Celsius warm compress was used to help shape and block the tear duct. The right eye served as a control. Then, at 0, 4, 8, 12, 24, 48, and 72 hours, 20 μL of 0.1% sodium fluorescein was instilled into both eyes and the timing was stopped when sodium fluorescein flowed out of the nose. Figure 2 The results in section d show that, compared to conventional eye drops (simulated with PBS solution), the thermosensitive tear plug (PP) can maintain embolism for up to 24 hours. Combined with the reversible temperature response of the thermosensitive gel, Figure 2 The results further showed that the tear plug could rapidly gel and exert its embolic effect under hot compresses, while it could revert to a sol state and be expelled through the nasal cavity under cold compresses. This characteristic not only effectively solves the clinical pain points of traditional tear plugs being prone to displacement and difficult to remove, but also avoids the problem of granulation tissue hyperplasia caused by long-term implantation by removing it as needed.

[0056] Furthermore, to investigate the solution-gel transition morphology of the thermosensitive gel, the gel appearance was recorded using a camera, and the microstructure of the solution-micelle-hydrogel was displayed using transmission electron microscopy (TEM). A schematic diagram of the micelle-gel transition mechanism was also drawn. Figure 3As shown, its temperature-sensitive properties are mainly due to the interaction between the hydrophilic and hydrophobic portions of the PEG-PLGA polymer chains. At 25°C, core-shell spherical micelles with a hydrophobic PLGA core and a hydrophilic PEG shell are discretely dispersed. When the temperature rises to 37°C, the micelles can transform into an interconnected three-dimensional network structure. This phase transition process can be explained by the thermodynamic formula ΔG = ΔH - T×ΔS: during the heating process, the entropy of the system decreases (ΔS < 0), becoming the core driving force for the system to transform from disordered dispersed micelles to an ordered three-dimensional network. From the perspective of molecular interaction mechanisms, the increase in temperature significantly enhances the aggregation tendency of the hydrophobic PLGA core, making it sufficient to overcome the hydration repulsion between molecules, thereby forming continuously cross-linked hydrophobic microregions; while the hydrophilic PEG segments always maintain good water compatibility, acting as hydrophilic spacers as the network framework to stabilize the dispersion system. This precisely tunable phase transition behavior, which combines rapid temperature response and stable network formation capability, lays an important foundation for the development of intelligent dot-like hydrogel embolization materials. When the ambient temperature reaches the phase transition threshold, the hydrophobic interactions and chain entanglement effects between polymer molecular chains are significantly enhanced, causing the system to transform from a fluid solution to a gel state. The gel has good temperature-sensitive reversibility; when the temperature drops below the phase transition temperature, the forces between molecular chains weaken, the gel network depolymerizes, and the system returns to a well-dispersed state with good fluidity.

[0057] Example 2: Safety assessment of PEG-PLGA thermosensitive tear plugs

[0058] To observe the ocular safety of the thermosensitive tear plug, 2.5 μL of commercially available artificial tears (sodium hyaluronate (SH)) were administered daily as a control. Short-term and long-term ocular irritation were tested in mice. On day 0, the thermosensitive tear plug (Gel) was used for embolization. 2.5 μL of 25 wt% PEG-PLGA micelle eye drops were administered daily to the ocular surface of C57BL / 6 mice. A 45°C warm compress was used to help shape and block the lacrimal duct. Based on the lacrimal duct occlusion test in Example 1, the medication was administered every two days. During this period, slit-lamp examination and corneal OCT were used to observe changes in the cornea and conjunctiva, and tear secretion test strips were used to test the embolization status. The slit-lamp fluorescence field was achieved by staining the corneal injury site with 1% sodium fluorescein eye drops. The slit-lamp bright-field image (…) Figure 4 a) and slit-lamp fluorescence ( Figure 4 As shown in b), the cornea remained clear and transparent on the day of application, two weeks later, and four weeks later, with no fluorescent dye adhering to the cornea and no signs of damage. Furthermore, regarding tear secretion, the use of the thermosensitive tear plug did not result in excessive tear production in the mice, demonstrating minimal irritation. Figure 4 c). Furthermore, from corneal OCT results ( Figure 4As shown in d), neither short-term nor long-term use of thermosensitive tear plugs caused corneal thickening or other abnormalities.

[0059] Example 3: Application of PEG-PLGA thermosensitive tear plugs in the treatment of dry eye in mice

[0060] To investigate the therapeutic effect of PEG-PLGA thermosensitive tear plugs on dry eye syndrome, a dry eye model was established in mice. The mice were initially treated with 0.4% benzalkonium chloride (BAC) solution twice daily for one week, successfully establishing the dry eye model. To maintain dry eye symptoms, 0.2% BAC solution was continued for another week, with the frequency reduced to once daily. The mice were divided into three groups: a negative control group receiving no treatment; a group receiving daily instillation of sodium hyaluronate (SH) and cyclosporine A (CsA, both commercially available clinical drugs for treating dry eye syndrome), 2.5 μL each time, for the entire treatment period; and a group receiving thermosensitive tear plug treatment, where cyclosporine A was added during the preparation of the PEG-PLGA micelles to achieve a final concentration consistent with commercially available cyclosporine A eye drops (0.05%), and plugs were inserted every two days. During treatment, the thermosensitive plugs degraded spontaneously and did not require removal. At different treatment time points, corneal transparency was examined using a slit lamp. Fluorescein staining was used to assess the degree of corneal damage in different groups, combining bright-field and fluorescent field observations from the slit lamp. Then, longitudinal sections of the mouse cornea at the treatment endpoint were captured using corneal OCT equipment. At different treatment time points, commercially available phenol red cotton thread was placed in the mouse conjunctival sac, and a timer was used for 30 seconds. The portion moistened by tear fluid turned red, and the length of the red cotton thread was measured with a ruler, representing the tear secretion volume. After treatment, the mice were euthanized, and their corneas were collected for HE staining (Hematoxylin-Eosin staining) and PAS staining (Periodic Acid-Schiffstaining) to observe the morphology of different corneal layers, the state of inflammation, and the distribution of conjunctival goblet cells (which maintain tear film stability) in the conjunctival epithelial cells. Results are shown below. Figure 5-6 .

[0061] Figure 5 This invention relates to the corneal transparency and corneal damage degree of mice after different treatments; where a represents corneal transparency under a slit-lamp bright field environment, and b represents the corneal damage degree under a slit-lamp fluorescent field environment. The results show that, compared to the positive control group treated with sodium hyaluronate-cyclosporine A (SH+CsA), the thermosensitive tear plug loaded with cyclosporine A (Gel+CsA) is more effective in restoring corneal transparency and alleviates corneal damage caused by dry eye to some extent.

[0062] Figure 6This diagram illustrates the tear secretion of mice after different treatments according to the present invention; where a represents the tear test results using phenol red cotton thread, and b is a statistical graph of the tear strip length indicated by the phenol red cotton thread. The results show that the CsA-loaded thermosensitive tear plugs have the function of reducing tear loss. In contrast, while the combined treatment strategy of cyclosporine A and artificial tears (sodium hyaluronate eye drops) can also alleviate dry eye symptoms, the recovery time is longer, and the efficacy is not as good as that of the CsA-loaded thermosensitive tear plugs.

[0063] Figure 7 This invention involves corneal OCT evaluation of mice after different treatments, as well as HE staining and PAS staining evaluation of collected eyeballs. In the figures, a represents corneal OCT, b represents corneal HE staining results, and c represents conjunctival PAS staining results. The results showed that the CsA-loaded thermosensitive tear plug relieved corneal swelling. HE staining revealed that, compared to the combined use of cyclosporine A and artificial tears (sodium hyaluronate eye drops), it more comprehensively cleared inflammation in all corneal layers (inflammatory cells were present in all corneal layers in both the untreated group and the HA+CsA group). PAS staining results showed that the CsA-loaded thermosensitive tear plug more effectively reduced the activity of conjunctival goblet cells.

[0064] In summary, thermosensitive tear plugs with PEG-PLGA as the core material can comprehensively avoid the clinical risks of traditional tear plugs, such as displacement and detachment, inflammation and infection, mechanical damage, and granulation tissue proliferation, thanks to their three core characteristics: thermosensitive in-situ gelation, excellent biocompatibility, and controllable biodegradability. At the same time, they can eliminate special adverse reactions such as paradoxical epiphora and temporary aggravation of symptoms, providing a safer and more stable new treatment option for the treatment of lacrimal duct embolism.

[0065] Example 4: Application of PEG-PLGA thermosensitive tear plugs in the treatment of dry eye in New Zealand rabbits

[0066] To examine the therapeutic effect of PEG-PLGA thermosensitive tear plugs on dry eye syndrome in a more complex and well-developed ocular model, a dry eye model was established using New Zealand rabbits. The rabbits were initially treated with 0.4% benzalkonium chloride (BAC) solution twice daily for two weeks, successfully establishing the dry eye model. To maintain dry eye symptoms, 0.4% BAC solution was continued for another week, with the frequency reduced to once daily. The mice were divided into three groups: a negative control group receiving no treatment; a group undergoing silicone tear plug implantation on the day of successful modeling, supplemented with cyclosporine A eye drops once daily for the entire treatment period; and a group receiving thermosensitive tear plug treatment, where cyclosporine A was added during the preparation of the PEG-PLGA micelles to achieve a final concentration consistent with commercially available cyclosporine A eye drops (0.05%), with plugs inserted every two days. During treatment, the thermosensitive plugs degraded spontaneously and did not require removal. At different treatment time points, corneal transparency was examined using a slit lamp. Fluorescein staining was used to assess the degree of corneal damage in different groups based on both bright-field and fluorescent fields observed under the slit lamp. At different treatment time points, commercially available ophthalmic tear film was placed on the conjunctival sac of mice, and a timer was used for 30 seconds. The portion wetted by tear fluid turned orange-red, and the length of the wetted area was measured as the tear secretion volume. Results are shown below. Figure 8-9 .

[0067] Figure 8 This invention relates to the corneal transparency and corneal damage degree of New Zealand rabbits after different treatments. Here, 'a' represents corneal transparency under a slit-lamp bright-field environment, 'b' represents the corneal damage degree under a slit-lamp fluorescent field environment, and 'c' represents the blinded scores collected from three clinicians based on the experimental results of 'a' and 'b'. The results show that, compared to the combined treatment effect of silicone tear plugs and cyclosporine A eye drops in the positive control group, the thermosensitive tear plugs (Gel+CsA) loaded with cyclosporine A are more effective in helping New Zealand rabbits restore corneal transparency, reduce corneal staining area, and alleviate corneal damage caused by dry eye to some extent.

[0068] Figure 9 This diagram illustrates tear secretion in mice after different treatments according to the present invention. In the diagram, 'a' represents the tear test results using ophthalmic tear testing filter paper, and 'b' is a statistical graph of the tear strip length indicated by the tear testing filter paper. The results show that the combined treatment strategy of cyclosporine A and silicone tear plugs, as well as the CsA-loaded thermosensitive tear plugs, effectively reduce tear loss. Based on the blinded assessment statistical graph of corneal health and the tear secretion statistical graph, the CsA-loaded thermosensitive tear plugs achieved a better therapeutic effect than commercially available silicone tear plugs.

[0069] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A PEG-PLGA thermosensitive tear plug, characterized in that, The PEG-PLGA thermosensitive tear plug is formed by a thermosensitive phase transition of eye drops prepared from PEG-PLGA polymer material; after the eye drops flow into the lacrimal punctum, a gel-like tear plug is formed in situ according to the physiological morphology of the lacrimal punctum.

2. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The number-average molecular weight of the PEG-PLGA thermosensitive polymer material is 750-1870.

3. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The molar ratio of PEG to PLGA in the PEG-PLGA thermosensitive polymer material is 1:4-1:

8.

4. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The concentration of PEG-PLGA thermosensitive polymer material in the eye drops is above 25 wt%.

5. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The pH value of the eye drops is 6.5-7.

5.

6. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The gelation temperature of the eye drops is greater than or equal to 37°C, and the gelation time is 1-2 seconds.

7. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The PEG-PLGA thermosensitive tear plug forms a solution at 30°C or less in 1-2 seconds.

8. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The eye drops are obtained by dissolving PEG-PLGA polymer material in physiological saline, followed by sterilization and stirring.

9. The PEG-PLGA thermosensitive tear plug according to claim 1, characterized in that, The eye drops also include small molecule water-soluble drugs, small molecule lipid-soluble drugs, and large molecule bioactive drugs.

10. The use of the PEG-PLGA thermosensitive tear plug according to any one of claims 1-9 in the preparation of a drug for treating dry eye syndrome.

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