A pharmaceutical composition synergistically targeting mmp-9 pathway and sting pathway and application thereof

Abstract

The application discloses a kind of drug composition of synergistic targeting MMP-9 path and STING path and application thereof, belong to the technical field of ophthalmic drugs.The drug composition includes the final concentration 5~90 μM of Marimastat, the final concentration 2.5~10 μM of SN-011, the final concentration 0.1 vol % of DMSO and sterile PBS buffer solution.The drug composition of the application can efficiently, safely treat moderate to severe dry eye, effectively improve tear film stability, repair corneal epithelial barrier, inhibit ocular surface chronic inflammation, while reducing the risk of disease recurrence.

Description

Technical Field

[0001] This invention belongs to the field of ophthalmic drug technology, specifically relating to a drug composition that synergistically targets the MMP-9 pathway and the STING pathway and its application. Background Technology

[0002] Dry eye disease (DED) is a prevalent chronic ocular surface disease worldwide. According to the third edition of the International Tear Film and Ocular Surface Society's Dry Eye Working Group report (TFOS DEWS III), the core pathological features of this disease are decreased tear film stability, increased tear osmotic pressure, ocular surface inflammation and damage, and abnormal ocular nerve sensation, which severely impair patients' visual quality and quality of life.

[0003] Currently, the main types of drugs used clinically to treat dry eye syndrome are artificial tears, anti-inflammatory immunomodulators, and matrix metalloproteinase inhibitors. Each type of drug has significant limitations. Artificial tears, represented by sodium hyaluronate eye drops, can only temporarily replenish tears and relieve dry eye symptoms. They cannot block the progression of ocular surface inflammation and the pathological process of tissue damage, and have limited therapeutic effects on moderate to severe dry eye syndrome.

[0004] Immune-boosting and anti-inflammatory drugs: such as 0.05% cyclosporine A eye drops, which exert anti-inflammatory effects by inhibiting T cell activation, but have problems such as slow onset of action, strong ocular surface irritation, and low bioavailability.

[0005] Matrix metalloproteinase inhibitors, represented by doxycycline, can inhibit MMP-9 activity and slow down corneal epithelial degradation to some extent. However, they have poor drug selectivity and insufficient penetrating ability on the ocular surface. Long-term use can also easily cause ocular flora imbalance.

[0006] Current clinical protocols generally suffer from three major technical deficiencies: First, they target a single inflammatory pathway, failing to simultaneously suppress inflammation and protect the corneal epithelium, thus making it difficult to break the vicious cycle of "tear hyperosmolarity → ocular surface inflammation → corneal barrier damage → further aggravation of inflammation." Second, their overall efficacy is limited. Dry eye is a disease caused by multiple pathways working together, and a single drug cannot cover all pathological stages. Current combination therapies lack synergistic design, merely adding up drug effects with minimal improvement. Third, safety and patient compliance are poor. Long-term use of hormones and broad-spectrum immunosuppressants can easily lead to risks such as increased intraocular pressure and systemic immune suppression. Most drugs have slow onset of action and significant ocular surface irritation, resulting in decreased patient compliance.

[0007] Recent studies have confirmed that overactivation of the cGAS-STING pathway is a key driver inducing and maintaining chronic inflammation of the ocular surface in dry eye. However, at present, no STING inhibitors have been approved for clinical treatment of dry eye, and there are no studies or public reports on the combined use of MMP-9 inhibitors and STING inhibitors for the prevention and treatment of dry eye. Summary of the Invention

[0008] Technical problem solved: In view of the shortcomings of existing dry eye treatment drugs, such as single target, poor efficacy, and inability to simultaneously intervene in the two core pathogenic pathways of MMP-9 and STING, this invention provides a pharmaceutical composition that synergistically targets the MMP-9 and STING pathways and its application. This composition can effectively and safely treat moderate to severe dry eye syndrome, effectively improve tear film stability, repair corneal epithelial barrier, inhibit chronic inflammation of ocular surface, and reduce the risk of disease recurrence.

[0009] Technical solution: In a first aspect, the present invention provides a pharmaceutical composition that synergistically targets the MMP-9 pathway and the STING pathway. The pharmaceutical composition comprises 5–90 μM Marimastat, 2.5–10 μM SN-011, 0.1 vol% DMSO, and sterile PBS buffer. The active ingredients of the pharmaceutical composition are Marimastat and SN-011, wherein Marimastat is an MMP-9 inhibitor and SN-011 is a STING inhibitor; 0.1 vol% DMSO is a solubilizer, and sterile PBS buffer is the base solvent.

[0010] Preferably, the final concentration of Marimastat in the pharmaceutical composition is 90 μM and the final concentration of SN-011 is 10 μM.

[0011] Preferably, the pharmaceutical composition is a topical ocular drop preparation.

[0012] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition described in the first aspect, comprising the following steps: S1. Take an appropriate amount of Marimastat, add DMSO and stir thoroughly until completely dissolved, then add sterile PBS buffer, vortex and mix well to obtain Marimastat stock solution; S2. Take an appropriate amount of SN-011, add DMSO to dissolve it completely, add sterile PBS buffer, and vortex mix after multiple sonic treatments. Under an optical microscope, observe that there are no visible crystals in the system, and the SN-011 mother liquor is obtained. S3. Mix the two mother liquors obtained in steps S1 and S2 according to the ratio, and vortex again until the system is homogeneous to obtain the target drug composition.

[0013] Thirdly, the present invention provides the use of the pharmaceutical composition described in the first aspect in the preparation of products for the prevention or treatment of dry eye syndrome.

[0014] Synergistic Mechanism of Action: Marimastat's mechanism of action: As a potent and selective MMP-9 inhibitor, it can significantly inhibit MMP-9 protein activity, reduce the degradation of corneal epithelial tight junction proteins, repair the corneal epithelial barrier structure, and improve tear hyperosmolarity. SN-011's mechanism of action: As a specific STING inhibitor, it can block the activation of the cGAS-STING pathway induced by damage-associated molecular patterns (DAMPs) such as mitochondrial DNA, downregulate the release of inflammatory factors such as IL-6, TNF-α, and IL-1β, and block the amplification effect of ocular surface inflammation cascade. The combination of the two drugs forms a bidirectional negative feedback synergistic regulatory system: Marimastat repairs the corneal epithelial barrier, reduces the release of damage-associated molecular patterns, and weakens the abnormal activation of the STING pathway from the source; SN-011 inhibits chronic inflammatory response, downregulates MMP-9 protein expression, and further prevents corneal epithelial degradation. The two drugs enhance each other, and the overall efficacy is significantly better than that of monotherapy. Beneficial effects

[0015] 1. Excellent safety (1) In vitro cell safety: SN-011 at concentrations of 2.5–10 μM and Marimastat at concentrations of 5–90 μM showed no significant toxicity to human corneal epithelial cells, with cell inhibition rate less than 20% and cell survival rate greater than 85%; the combination system did not crystallize and was suitable for ocular surface administration; the combined use did not increase cytotoxicity, but instead had a slight protective effect on cells; after pharmacodynamic screening, the optimal combination concentration of SN-011 was determined to be 10 μM, and the preferred working concentration of Marimastat was 90 μM; (2) In vivo ocular safety: After 14 days of continuous ocular administration, the Draize score of the mouse ocular surface was ≤1. No local irritation symptoms such as corneal opacity, iris congestion, or conjunctival edema were observed. The ocular safety was not statistically different from that of the pbs group and the 0.05% cyclosporine A group. (3) Systemic safety: After 14 days of continuous administration, the mice in each group had normal weight gain, no animal deaths, and no obvious systemic toxicity was observed.

[0016] 2. Significantly improves core clinical indicators of dry eye The pharmaceutical composition of this invention can significantly increase tear secretion in dry eye model animals, significantly prolong tear film breakup time (BUT), and greatly reduce corneal epithelial damage; its efficacy is significantly better than that of the PBS control group and the commonly used 0.05% cyclosporine A eye drops.

[0017] 3. Highly effective in repairing corneal tissue structure HE staining of the cornea showed that the corneal epithelial cells in the dry eye model group were disordered and severely damaged. After intervention with this composition, the corneal epithelial surface was smooth, the cells were arranged in a regular manner, the number of epithelial cells and the thickness of the corneal epithelium were significantly restored, and the corneal tissue structure was restored to a near-normal level. The repair effect was better than that of the single drug treatment group.

[0018] 4. Effectively inhibits inflammatory response and matrix degradation Immunohistochemical analysis confirmed that this combination therapy significantly downregulated the protein expression of IL-1β, IL-6, TNF-α, MMP-3, and MMP-9 in corneal tissue. Its inhibitory effect on inflammatory factors and matrix degradation-related proteins was significantly better than that of SN-011 monotherapy, Marimastat monotherapy, doxycycline, genistein, and cyclosporine A.

[0019] 5. Dual pathway synergy to block pathological circulation Hyperosmolar environments can induce abnormally high expression of STING protein in human corneal epithelial cells; Marimastat can downregulate STING protein expression, and when used in combination with SN-011, it synergistically inhibits the cGAS-STING pathway and the MMP-9 pathway, blocking the pathological process of dry eye disease from multiple aspects such as tear secretion, tear film stability, corneal barrier, and inflammation regulation, and has good potential for clinical translation. Attached Figure Description

[0020] Figure 1 The effects of different concentrations of SN-011, different concentrations of Marimastat alone, and different concentrations of Marimastat in combination with 10 μM SN-011 on the inhibition rate of human corneal epithelial cells were investigated; data are expressed as mean ± standard error (SEM), n=3; Figure 2 The intervention effects of each experimental group of eye drops on dry eye model mice are shown. A represents representative corneal fluorescence staining images under a slit lamp; B represents corneal fluorescence staining scores; C represents tear film breakup time (BUT) results; and D represents tear secretion volume measured using the phenol red cotton thread method. Each group has n=5. Data are expressed as mean ± standard deviation (SD). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Figure 3 HE staining results and quantitative analysis of corneal tissue from each group of mice; where A is a representative image of corneal HE staining; B is the count of corneal epithelial cells; C is the count of corneal epithelial thickness; the scale is 50 μm, n=3 per group, and the data are expressed as mean ± standard deviation (SD), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; Figure 4Immunohistochemical quantitative results of IL-1β, IL-6, TNF-α, MMP3, and MMP9 protein expression in corneal tissue; n=3 per group, data are expressed as mean ± standard deviation (SD), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; Figure 5 This study presents Western blot results and grayscale quantification of STING protein expression in human corneal epithelial cells using Marimastat and SN-011 alone and in combination under hyperosmolar conditions. β-actin was used as an internal reference. Data are expressed as mean ± standard deviation (SD), *p<0.05, **p<0.01. Detailed Implementation

[0021] The present invention will be described in detail below with reference to specific embodiments: Experimental materials and instruments Experimental materials: Marimastat (MMP-9 inhibitor, purity ≥98%); SN-011 (STING inhibitor, purity ≥98%); DMSO, sterile PBS buffer (pH=7.2±0.1, osmotic pressure 312 mOsM, matching the physiological osmotic pressure of human tears); all standard reagents used in the experiment were of analytical grade. Experimental apparatus: Equipment includes an electronic balance with an accuracy of 0.01 mg, an ultrasonic homogenizer, a pH meter, a 0.22 μm sterile microporous filter membrane, an optical microscope, a slit-lamp microscope, an ELISA reader, a paraffin microtome, and an imaging analysis system.

[0022] Example 1: Preparation of the pharmaceutical composition Weigh out a sufficient amount of Marimastat, add DMSO and stir until completely dissolved, add sterile PBS buffer, and vortex thoroughly to obtain the Marimastat stock solution; Weigh out a sufficient amount of SN-011, add DMSO and stir until completely dissolved, add sterile PBS buffer, and after multiple sonic treatments, vortex mix. Confirm under an optical microscope that there are no visible crystals to obtain the SN-011 mother liquor. The two solutions were mixed and vortexed to achieve a final concentration of 90 μM for Marimastat, 10 μM for SN-011, and 0.1% for DMSO. PBS was used as the solvent to obtain the pharmaceutical composition of the present invention.

[0023] Example 2: Security Verification 1. In vitro cell safety verification The SN-011 mother liquor prepared in Example 1 was diluted to 2.5–10 μM, and the Marimastat mother liquor was diluted to 5–90 μM for safety verification tests.

[0024] CCK-8 assay: The cytotoxicity of different concentrations of sn-011 to immortalized human corneal epithelial cells (HCECs) was assessed using the Cell Counting Kit-8 (CCK-8). HCECs were maintained in DMEM / F12 medium and cultured at a single-cell suspension concentration of 1×10⁻⁶ cells / cells. 5 Cells were seeded at a density of [number] cells / mL in 96-well plates and cultured at 37°C, 5% CO2, and 95% humidity. After treatment with different concentrations of Marimastat and sn-011 for 24 hours, the cells were co-cultured in the dark with medium containing 10% CCK-8 solution for 2 hours. The optical density (OD) was recorded at 450 nm. Cell survival curves were obtained to determine the appropriate ophthalmic drop concentrations of Marimastat and sn-011 for HCEC treatment.

[0025] Experimental results are as follows Figure 1 As shown, under the experimental conditions, sn-011 was completely soluble at a concentration of 10 μM; at concentrations higher than this, the drug precipitated crystals due to insufficient solubility. Therefore, 10 μM was determined to be the maximum soluble concentration at which sn-011 would not precipitate. Within this concentration range, CCK-8 results showed that cell viability exceeded 100% in all concentration groups, indicating that sn-011 had no significant cytotoxicity.

[0026] To evaluate the cytotoxicity of marimastat, we first performed CCK-8 assays over a wide concentration range. The results showed that cell viability gradually decreased with increasing marimastat concentration. When the marimastat concentration reached or exceeded 100 μM, the viability dropped below 75%, indicating that the drug began to exhibit significant cytotoxicity at this concentration. To further clarify the safe concentration window of marimastat, we narrowed the concentration gradient and performed a second CCK-8 assay within the 50-90 μM range. Within the 50-90 μM concentration range, the inhibitory effect of marimastat alone on cell viability was concentration-dependent. After adding 10 μM sn-011, the cell viability in the combination therapy group was slightly higher than that in the marimastat monotherapy group at all concentration points. At the highest tested concentration of 90 μM, the viability of the marimastat monotherapy group was 75%, and the viability of the combination therapy group was 78%, with no statistically significant difference (P>0.05). The above results indicate that 10 μM sn-011 did not synergistically enhance marimastat-induced cytotoxicity in the 50-90 μM concentration range; instead, it showed a slight protective trend. Based on this dose-response relationship, subsequent experiments selected three marimastat concentrations of 10, 50, and 90 μM for mechanism investigation, where 10 μM represents the concentration of sn-011 that is non-cytotoxic and does not precipitate, and 50-90 μM represents the working range in which marimastat can induce observable toxic effects.

[0027] In the single-drug trial of sn-011, the 2.5, 5, and 10 μM groups showed dose-dependent effects, with the 10 μM group showing the most significant therapeutic effect on dry eye (P<0.05 vs 2.5 μM). Therefore, 10 μM was selected as the fixed concentration of sn-011 in combination therapy.

[0028] 2. In vivo ocular safety A dry eye model was established using C57BL / 6 mice (6-8 weeks old, female). Mice were purchased from Suzhou Spefolk Pharmaceutical Co., Ltd. These mice were housed in the SPF-grade facility of the Animal Laboratory at China Pharmaceutical University. This study was approved by the Laboratory Animal Ethics Committee of China Pharmaceutical University (YSL-202506086, Nanjing, Jiangsu Province, China). All experimental procedures strictly adhered to the American Association for Research in Vision and Ophthalmology (ARVO) statement regarding the use of animals in ophthalmological and vision research. The specific experimental procedure was carried out in accordance with the literature (Wilhelmus KR. The Draize eye test. Surv Ophthalmol. 2001 May-Jun;45(6):493-515. doi: 10.1016 / s0039-6257(01)00211-9. PMID: 11425356.). After 14 consecutive days of administration, the Draize score of the ocular surface of mice in each group was ≤1. Under slit lamp observation, there were no irritation reactions such as corneal opacity, iris congestion, or conjunctival edema. The ocular safety was not statistically different from that of the pbs group and the 0.05% cyclosporine A group.

[0029] 3. Overall safety After 14 days of continuous administration, mice in each administration group showed normal weight gain and no deaths, with no significant difference from the control group and no systemic toxicity.

[0030] Example 3: In vivo efficacy verification Animal experiments were conducted using a dry eye model mouse. After 3 days of acclimatization, mice were subcutaneously injected with scopolamine hydrobromide (2.5 mg / mL, PBS, 0.1 mL / injection) four times daily (9:00, 12:00, 14:00, and 17:00). On day 10 of modeling, corneal fluorescein staining and tear secretion tests were performed. A positive corneal fluorescein staining result and a tear secretion test result of <7 mm / 15 s were considered a successful dry eye model. After successful modeling, each group received ophthalmic drops for 14 days. The following treatment groups received 5 μL eye drops twice daily (9:00 and 17:00): PBS treatment group, cyclosporine treatment group (0.05%), cyclosporine treatment group, Marimastat treatment group (10 μM, 50 μM, 90 μM), sn-011 treatment group (2.5 μM, 5 μM, 10 μM), and combined treatment group (2.5 μM sn-011 + 90 μM Marimastat, 5 μM sn-011 + 90 μM Marimastat, 10 μM sn-011 + 90 μM Marimastat). After the experiment, eye tissue from each group of mice was collected on dry ice, fixed in paraformaldehyde, and embedded.

[0031] Statistical analysis was performed using imageJ and GraphPad Prism10 software. One-way ANOVA was used for measurement data (which conform to a normal distribution), and P < 0.05 was considered statistically significant.

[0032] The results are as follows Figure 2 As shown: Compared with the negative normal mouse group (ctrl), the PBS group showed more obvious corneal fluorescein staining, significantly reduced tear secretion and tear film breakup time, and significantly increased corneal fluorescein staining score; most indicators in the drug intervention groups improved. Compared with the PBS group, the marimastat 90 μM and SN-011 10 μM + marimastat 90 μM groups significantly reduced corneal fluorescein staining, increased tear secretion, prolonged tear film breakup time, and reduced corneal fluorescein staining score (P<0.001), and were more effective than the clinically commonly used 0.05% cyclosporine (CS-A) group. Compared with marimastat monotherapy, SN-011 monotherapy, and clinically commonly used cyclosporine A eye drops, the combination composition of this invention (SN-011 10 μM + marimastat 90 μM) has better overall efficacy, and can simultaneously achieve multiple effects such as anti-inflammation, corneal barrier repair, and tear film stabilization, making it an ideal candidate drug for the treatment of dry eye syndrome.

[0033] Example 4: Verification of Corneal Tissue Structure Repair Effect HE staining experiment method: Mouse eyeballs in each group were fixed with paraformaldehyde, dehydrated, embedded in paraffin, sectioned, dewaxed in xylene I, II, and III for 10 min each, then placed in 100%, 95%, 70%, 80%, and 70% alcohol solutions for 5 min each, followed by 1 min in distilled water; stained in hematoxylin for about 5 min, washed with water until water droplets dripped from the section and it was transparent and colorless; the section was placed in differentiation solution for 1-2 s for differentiation, rinsed with running water; blued for 5-10 s, rinsed with running water, and the nuclei were observed for staining. 70% alcohol for 30 s, eosin for 1-2 min, 70% alcohol for 10 s, 80%, 90%, and 95% alcohol for 30 s each, passed through two tanks of anhydrous ethanol for 1 min, the section was placed in xylene I and II for 1 min each, the cytoplasm was observed for staining, and the slides were mounted.

[0034] The results are as follows Figure 3 As shown: the model group showed disordered corneal epithelial arrangement and significant cell damage; the SN-011+Marimastat group showed smooth corneal epithelial surface, orderly cell arrangement, and near-normal structure; it can significantly increase the number of corneal epithelial cells, increase epithelial thickness, and promote the complete recovery of tissue structure, with better effects than the single-drug treatment group; HE staining results showed that after 14 days of treatment, the corneal epithelial and stromal cells in the PBS group were disordered, and the corneal epithelial cells were damaged. The number and thickness of corneal epithelial cells were significantly lower than those in the control group (P<0.0001), while the drug-treated groups all showed varying degrees of significant recovery (P<0.0001). Among them, the sn-011 10 μM combined with marimastat 90 μM group showed strong recovery ability: the corneal epithelial surface was smooth, the number of epithelial cells increased, the morphology gradually normalized, the cells were neatly arranged, the thickness of the corneal epithelial layer increased, and corneal epithelial degeneration was significantly prevented.

[0035] Example 5: Validation of the inhibitory effect on inflammation and matrix degradation Immunohistochemical assay: Mouse eyeballs were fixed with paraformaldehyde, dehydrated, embedded, sectioned at 3 μm, and dried overnight at 64℃. Paraffin sections were dewaxed with xylene I and II for 10 min each, then immersed in 100%, 95%, 85%, 70%, and 50% ethanol solutions for 5 min each, followed by immersion in distilled water for 1 min. Washed three times with PBST for 5 min each. Microwave repair was performed on high for 3 min; sections were then immersed in repair solution on low for 10 min, followed by enzyme repair at 37℃ for 20 min. Sections were allowed to cool naturally to room temperature and washed three times with PBST for 5 min each. Endogenous peroxidase inhibitors were added, incubated at room temperature for 10 min, and washed three times with PBST for 5 min each. Non-specific inhibitors were added, incubated at room temperature for 10 min, then aspirated without washing. Primary antibodies against IL-1β, IL-6, TNF-α, MMP-3, and MMP-9 were added, and incubated overnight at 4℃. The sections were removed from the refrigerator and allowed to return to room temperature for 40 min, then washed three times with PBST for 5 min each. Add biotin-labeled secondary antibody, incubate at room temperature for 10 min, then wash three times with PBST for 5 min each time. Add SP (streptomycin antibiotic protein-peroxidase), incubate at room temperature for 10 min, then wash three times with PBST for 5 min each time. After preparing the DAB chromogenic reagent, add it to the slide, incubate at room temperature, and check the reaction time under a microscope. Rinse with running water. Counterstain with Mayer hematoxylin for 30 s, then with blue solution for 5 min, and rinse with tap water. Pass through three baths of anhydrous ethanol and two baths of xylene / environmentally friendly clearing solution, then mount the slide.

[0036] Immunohistochemical results as follows Figure 4 As shown, combined medication significantly inhibited the expression of inflammatory factors IL-1β, IL-6, TNF-α, MMP-3, and MMP-9 in corneal tissue. Among them, the SN-011+Marimastat group showed the strongest inhibitory effect on IL-1β, IL-6, TNF-α, MMP-3, and MMP-9, which was significantly better than the single-drug groups of SN-011, single-drug groups of Marimastat, doxycycline, genistein, and cyclosporine.

[0037] Example 6: Validation of synergistic effects and clinical potential Human corneal epithelial cells (HCET) were exposed to normal environment (approximately 312 mOsM, con), hyperosmolar environment (550 mOsM, hyper), and hyperosmolar environment with different drugs (marimastat 90 μM (ma), sn-011 10 μM (sn), sn-011 10 μM + marimastat 90 μM (ma + sn)) for 24 h. Proteins were then extracted for Westem blot analysis, using β-actin as an internal control. Imagelab software was used to analyze grayscale values ​​and calculate the relative expression level of STING protein. Statistical significance was assessed using one-way ANOVA. Data are expressed as mean ± variance (SD), *p < 0.05, **p < 0.01.

[0038] Western blot results are as follows Figure 5 As shown, after 24 hours of hyperosmolar stimulation of HCET cells, STING protein expression was significantly increased compared to the normal group (p<0.05). After drug administration, STING protein expression levels decreased to varying degrees in all groups, with the marimastat group and the combined drug group showing the most significant decreases (p<0.01). In summary, these findings indicate that marimastat and the combined drug administration can repair the cornea and alleviate dry eye symptoms by downregulating STING protein expression.

[0039] SN-011 inhibits the cGAS-STING pathway and reduces inflammation; Marimastat inhibits MMP-9 and protects the epithelium. The combination of the two drugs produces a significant synergistic effect.

[0040] The pharmaceutical composition of this invention can simultaneously increase tear production, stabilize the tear film, repair the epithelium, inhibit inflammation, and block the pathological process of dry eye at multiple targets and stages, and is expected to become a novel dry eye treatment solution superior to existing clinical drugs.

[0041] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition synergistically targeting the MMP-9 pathway and the STING pathway, characterized in that: The pharmaceutical composition comprises 5–90 μM Marimastat, 2.5–10 μM SN-011, 0.1 vol% DMSO, and sterile PBS buffer.

2. The pharmaceutical composition according to claim 1, characterized in that: The final concentration of Marimastat in the pharmaceutical composition is 90 μM, and the final concentration of SN-011 is 10 μM.

3. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition is a topical ophthalmic drop preparation.

4. A method for preparing the pharmaceutical composition according to any one of claims 1-3, characterized in that, Includes the following steps: S1. Take an appropriate amount of Marimastat, add DMSO and stir thoroughly until completely dissolved, then add sterile PBS buffer, vortex and mix well to obtain Marimastat stock solution; S2. Take an appropriate amount of SN-011, add DMSO to dissolve it completely, add sterile PBS buffer, and vortex mix after multiple sonic treatments. Under an optical microscope, no crystals are visible to the naked eye in the system, thus obtaining the SN-011 mother liquor. S3. Mix the two mother liquors obtained in steps S1 and S2 according to the ratio, and vortex again until the system is homogeneous to obtain the target drug composition.

5. Use of the pharmaceutical composition according to any one of claims 1-3 in the preparation of products for the prevention or treatment of dry eye syndrome.

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