An ophthalmic pharmaceutical composition and a pharmaceutical preparation containing the same

Abstract

The application relates to the technical field of eye medicines, and particularly discloses an eye medicine composition and a medicinal preparation containing the composition, wherein the eye medicine composition contains a polysulfated mucopolysaccharide or a pharmaceutically acceptable salt thereof and hyaluronic acid or a pharmaceutically acceptable salt thereof. The polysulfated mucopolysaccharide is combined with sodium hyaluronate and applied to the preparation of medicines for treating ophthalmic diseases, so that dry eye, corneal injury or filtering bleb scarring after glaucoma filtering surgery can be effectively improved, and a new method for treating related ophthalmic diseases is developed.

Description

Technical Field

[0001] This application relates to the field of ophthalmic pharmaceutical technology, and more specifically, to an ophthalmic pharmaceutical composition and a pharmaceutical preparation containing the composition. Background Technology

[0002] Mucopolysaccharide polysulfate (MPS) is a heparin-like substance with known pharmacological properties including significant anti-inflammatory, anticoagulant, antithrombotic, microcirculation-improving, and tissue repair and regeneration-promoting effects. Currently, its clinical applications are mainly limited to dermatology and vascular surgery, such as for treating superficial phlebitis, contusions, hematomas, and inhibiting scar hyperplasia. However, in ophthalmology, the pathophysiological processes of many diseases are highly correlated with the mechanism of action of MPS, yet significant therapeutic gaps and limitations remain.

[0003] Dry Eye Syndrome and Corneal Injury: Dry eye syndrome is a multifactorial disease characterized by chronic ocular surface inflammation and tear film instability, with its core pathological process being a vicious cycle of "damage-inflammation." The repair process of corneal damage (such as trauma or surgical wounds) requires rapid anti-inflammatory measures and the promotion of high-quality, scarless healing. Existing treatments (such as artificial tears and anti-inflammatory drugs) often target only one specific area and are insufficient to comprehensively address the complex pathological process. Dry eye syndrome is a common multifactorial ocular surface disease characterized by insufficient tear secretion or excessive evaporation leading to tear film homeostasis imbalance, accompanied by ocular discomfort symptoms, inflammatory reactions, ocular surface epithelial damage, and neurosensory abnormalities. Globally, the prevalence of dry eye syndrome is as high as 5% to 50%, severely impacting patients' quality of life. Its core pathophysiological mechanism is considered to be a vicious cycle of "inflammation-damage": tear film instability exacerbates ocular surface friction and high osmotic pressure, triggering epithelial cell damage and apoptosis, which in turn activates the immune system and releases a large number of inflammatory factors (such as IL-1β, IL-6, TNF-α), while inflammation further damages lacrimal gland function and goblet cells, exacerbating tear film instability and forming a vicious cycle.

[0004] Currently, there are many limitations in the clinical treatment of dry eye:

[0005] Artificial tears: As a first-line basic treatment, they primarily provide temporary relief of symptoms through physical lubrication and hydration. However, their effect is short-lived, requiring frequent application. For moderate to severe dry eye syndrome, especially in patients with significant inflammation, simple lubrication is far from sufficient to control disease progression.

[0006] Hyaluronic acid (HA) eye drops: HA is a natural glycosaminoglycan widely used in high-end artificial tears due to its excellent biocompatibility, water retention, and viscoelasticity. It can form a protective hydration film on the ocular surface, prolonging tear retention time and promoting corneal epithelial repair. Although HA is superior to traditional artificial tears in lubrication and repair, its anti-inflammatory effect is relatively weak, and its ability to intervene in the core inflammatory aspects of moderate to severe dry eye is limited.

[0007] Topical anti-inflammatory drugs: Corticosteroids: such as fluorometholone and clotiprednisolone, can quickly and effectively suppress inflammation, but long-term use can cause serious side effects such as increased intraocular pressure, cataracts, and secondary infections, which limits their application in the management of chronic diseases.

[0008] Immunosuppressants, such as cyclosporine A (CsA) and Lifitegrast, are currently the mainstream prescription drugs for treating moderate to severe dry eye. They control inflammation by inhibiting T-cell activation or integrin signaling pathways. However, these drugs generally have a slow onset of action (usually taking weeks to months), significant individual variability in efficacy, and are often accompanied by adverse reactions such as eye irritation and burning, leading to poor patient compliance.

[0009] Postoperative scarring of the filtering bleb after glaucoma surgery: Glaucoma filtration surgery is an effective method for lowering intraocular pressure, but its long-term success rate is limited by postoperative fibrosis and scarring of the filtering bleb. Currently, antimetabolites such as mitomycin C are commonly used clinically to inhibit scarring, but these drugs have potential risks such as strong cytotoxicity and corneal endothelial damage. Finding a safer and gentler antifibrotic drug to maintain the long-term patency of the filtration channel is an urgent clinical need.

[0010] In summary, although existing cream formulations of MPS explicitly prohibit contact with the eyes, its unique multiple pharmacological effects make it a highly promising candidate molecule for developing novel ophthalmic drugs. There is an urgent need to develop a safe, effective, and appropriately formulated MPS ophthalmic drug composition to meet the aforementioned unmet clinical needs. Summary of the Invention

[0011] To address the aforementioned technical issues, this application provides a method for combining polysulfated mucopolysaccharide with sodium hyaluronate in the preparation of drugs for treating ophthalmic diseases. This method can effectively improve dry eye syndrome, corneal damage, or scarring of the filtering bleb after glaucoma filtration surgery, thus opening up new avenues for the treatment of related ophthalmic diseases.

[0012] Firstly, to achieve the above objectives, this application adopts the following technical solution:

[0013] An ophthalmic pharmaceutical composition comprising polysulfated mucopolysaccharide or a pharmaceutically acceptable salt thereof, and hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0014] More preferably, the composition comprises polysulfated mucopolysaccharide and sodium hyaluronate, wherein the polysulfated mucopolysaccharide has a weight percentage concentration of 0.1%-1.0% and the sodium hyaluronate has a weight percentage concentration of 0.1%-0.5%.

[0015] More preferably, the polysulfonic acid mucopolysaccharide has a weight percentage concentration of 0.3%, and the sodium hyaluronate has a weight percentage concentration of 0.2%.

[0016] More preferably, the weight ratio of the polysulfated mucopolysaccharide to sodium hyaluronate is 1:(0.5-1).

[0017] More preferably, compared to using polysulfated mucopolysaccharide or sodium hyaluronate alone, the composition can significantly prolong the tear film breakup time in a rabbit model of dry eye and reduce the corneal fluorescein staining score.

[0018] More preferably, compared to using polysulfated mucopolysaccharide or sodium hyaluronate alone, the composition can significantly inhibit the expression levels of IL-6 and TNF-α inflammatory factors induced by lipopolysaccharide in human corneal epithelial cells.

[0019] More preferably, compared to using polysulfated mucopolysaccharide or sodium hyaluronate alone, the composition can significantly improve the migration and proliferation rate of human corneal epithelial cells.

[0020] Secondly, to achieve the above objectives, this application also adopts the following technical solution:

[0021] A pharmaceutical preparation containing the above-mentioned ophthalmic pharmaceutical composition, wherein the pharmaceutical preparation is an eye drop, an ophthalmic gel, an ophthalmic ointment, an ophthalmic implant, or an intraocular injection.

[0022] More preferably, the pharmaceutical preparation further includes pharmaceutically acceptable excipients, including but not limited to:

[0023] Thickeners: Used to increase viscosity and prolong the residence time of drugs on the ocular surface, such as carbomer, hydroxypropyl methylcellulose, polyvinyl alcohol, etc.

[0024] Buffers: Used to adjust the pH value to a range that is tolerable to the eyes (such as pH 6.5-7.5), such as phosphate buffer, borate buffer, etc.

[0025] Isotonic regulators: used to adjust the osmotic pressure to be isotonic with tears, such as sodium chloride and glycerin.

[0026] Preservatives: used to prevent microbial contamination, such as benzalkonium chloride, polyquaternium-1, etc.

[0027] In summary, this application has the following beneficial effects:

[0028] Synergistic effect and excellent therapeutic effect: Through the synergistic effect of polysulfated mucopolysaccharide and sodium hyaluronate, the composition of this application shows superior effects in stabilizing the tear film, fighting inflammation and repairing damage, which are far superior to single preparations or their simple sum.

[0029] Multi-target, comprehensive treatment: The composition of this application simultaneously addresses the three major problems of dry eye syndrome: lubrication, chemical inflammation, and tissue damage, providing a more comprehensive treatment solution.

[0030] Rapid onset of action and good tolerability: Compared with immunosuppressants, the composition of this application has a faster onset of action, and because both MPS and HA have good biocompatibility, their ocular irritation is extremely low, and patients tolerate them well, making them suitable for long-term use.

[0031] This application demonstrates that by combining polysulfated mucopolysaccharide with sodium hyaluronate, it can significantly improve tear film stability and exhibits effects far exceeding those of single-ingredient preparations or their simple sum in terms of anti-inflammatory and damage repair. Attached Figure Description

[0032] Figure 1 A comparison of tear film breakup time (TBUT) in different groups of mice;

[0033] Figure 2 A comparison chart of corneal fluorescein staining (CFS) scores for mice in each group;

[0034] Figure 3 A comparison of the inhibition rates of the inflammatory factor IL-6 in human corneal epithelial cells from different groups;

[0035] Figure 4 This is a comparison of the inhibition rates of the inflammatory factor NTF-α in corneal epithelial cells of different groups. Detailed Implementation

[0036] The following specific examples illustrate the implementation of this application. Those skilled in the art can easily understand other advantages and effects of this application from the content disclosed in this specification. This application can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of this application.

[0037] Furthermore, it should be understood that the one or more method steps mentioned in this application do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise stated. Moreover, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and is not intended to limit the order of the method steps or limit the scope of implementation of this application. Changes or adjustments to their relative relationships, without substantially altering the technical content, shall also be considered as within the scope of implementation of this application.

[0038] Unless otherwise specified, the experimental conditions used in the examples are generally in accordance with conventional conditions in the art or the conditions recommended by the reagent company. Unless otherwise specified, the materials and reagents used in the examples can be purchased commercially.

[0039] Polysulfated mucopolysaccharide: Source: Nanjing Dichang Pharmaceutical Technology Co., Ltd.; Specific rotation: -13.6° (limit: -10°~-15°), Molar ratio of sulfate to carboxyl group: 3.5 (limit: ≥3.0), Molecular weight and molecular weight distribution: Weight average molecular weight: 9046 (weight average molecular weight limit: 5000~15000), Content determination: 98.8% (limit: 90.0%~110.0%).

[0040] Sodium hyaluronate: Source: Bloomage Biotechnology Co., Ltd.; Intrinsic viscosity: 16.8 (limit: 11.8 dL / g~19.5 dL / g), average molecular weight: 968068 (limit: 600000~1200000); Content determination: 100.2% (limit: contains sodium hyaluronate (C 14 H 20 NNaO 11 ) n It should be 95.0% to 105.0%.

[0041] Example

[0042] Example 1: Preparation of 0.3% MPS / 0.2% HA compound eye drops

[0043] Formula: For a preparation of 1000 mL, see Table 1 for the formula.

[0044] Table 1

[0045] Element Dosage effect Polysulfonic acid mucopolysaccharide 3.0g Active ingredients Sodium hyaluronate 2.0g Active ingredients Sodium chloride 7.0g isotonic regulator disodium hydrogen phosphate Appropriate amount buffer Sodium dihydrogen phosphate Appropriate amount buffer Benzalkonium chloride (50% solution) 0.2ml preservative Water for Injection Add to 1000ml solvent

[0046] Preparation process: a. Take 800ml of water for injection, heat to 60℃, and add sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate sequentially, stirring to dissolve. b. Cool to room temperature, add polysulfated mucopolysaccharide and sodium hyaluronate, and continue stirring until completely dissolved and transparent. c. Add benzalkonium chloride solution and mix well. d. Adjust the pH to 7.0±0.2 using 0.1M hydrochloric acid or 0.1M sodium hydroxide solution. e. Make up to 1000ml with water for injection and mix well. f. Filter sterilely using a sterile filter membrane with a pore size of 0.22μm. g. In a Class 100 laminar flow clean environment, aseptically fill the filtrate into pre-sterilized eye drop bottles, 5ml per bottle, and seal. h. Conduct quality inspection; the finished product is obtained after passing the inspection.

[0047] Example 2: Preparation of 0.5% MPS / 0.3% HA compound ophthalmic gel

[0048] Formula: For a preparation of 1000 mL, see Table 2 for the formula.

[0049] Table 2

[0050] Element Dosage effect Polysulfonic acid mucopolysaccharide 0.5g Active ingredients Sodium hyaluronate 0.3g Active ingredients Carbomer 974P 0.25g gel matrix glycerin 2.0g Moisturizers, isotonic regulators Sodium hydroxide Appropriate amount pH adjuster Water for Injection Add to 100g solvent

[0051] Preparation process: Carbomer is dispersed in water for injection and, after complete hydration, glycerol, MPS, and HA are added sequentially and stirred until homogeneous. The pH is adjusted to 7.4 with sodium hydroxide solution to form a transparent gel. After terminal moist heat sterilization, it is aseptically filled into dedicated ophthalmic gel tubes.

[0052] Preparation of Comparative Example 1: 0.2% HA Eye Drops

[0053] Formula: For a preparation of 1000 mL, see Table 3 for the formula.

[0054] Table 3

[0055] Element Dosage effect Sodium hyaluronate 2.0g Active ingredients Sodium chloride 7.0g isotonic regulator disodium hydrogen phosphate Appropriate amount buffer Sodium dihydrogen phosphate Appropriate amount buffer Benzalkonium chloride (50% solution) 0.2ml preservative Water for Injection Add to 1000ml solvent

[0056] Preparation process: a. Take 800ml of water for injection, heat to 60℃, and add sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate sequentially, stirring to dissolve. b. Cool to room temperature, add sodium hyaluronate, and continue stirring until completely dissolved and transparent. c. Add benzalkonium chloride solution and mix well. d. Adjust the pH to 7.0±0.2 using 0.1M hydrochloric acid or 0.1M sodium hydroxide solution. e. Make up to 1000ml with water for injection and mix well. f. Filter sterilely using a sterile filter membrane with a pore size of 0.22μm. g. In a Class 100 laminar flow clean environment, aseptically fill the filtrate into pre-sterilized eye drop bottles, 5ml per bottle, and seal. h. Conduct quality inspection; the finished product is obtained after passing the inspection.

[0057] Comparative Example 2: Preparation of 0.3% MPS Eye Drops

[0058] Formula: For a preparation of 1000 mL, see Table 4 for the formula.

[0059] Table 4

[0060]

[0061]

[0062] Preparation process: a. Take 800ml of water for injection, heat to 60℃, and add sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate sequentially, stirring to dissolve. b. Cool to room temperature, add polysulfated mucopolysaccharide, and continue stirring until completely dissolved and transparent. c. Add benzalkonium chloride solution and mix well. d. Adjust the pH to 7.0±0.2 using 0.1M hydrochloric acid or 0.1M sodium hydroxide solution. e. Make up to 1000ml with water for injection and mix well. f. Filter sterilely using a sterile filter membrane with a pore size of 0.22μm. g. In a Class 100 laminar flow clean environment, aseptically fill the filtrate into pre-sterilized eye drop bottles, 5ml per bottle, and seal. h. Conduct quality inspection; the finished product is obtained after passing the inspection.

[0063] Testing and Experiment

[0064] Eye drops and ophthalmic gels work in a similar manner, differing only in dosage form and viscosity. Therefore, this application conducts efficacy testing experiments on eye drops, with the specific test items as follows.

[0065] Test 1: The efficacy of 0.3% MPS / 0.2% HA compound eye drops in treating dry eye syndrome.

[0066] To verify the synergistic effect of the composition of the present invention, a benzalkonium chloride (BAC)-induced rabbit dry eye model was established.

[0067] 1. Experimental Animals and Grouping: Forty healthy New Zealand white rabbits were randomly divided into four groups of 10 each.

[0068] Group A (model control group): Administered physiological saline.

[0069] Group B (HA control group): Administered 0.2% HA eye drops prepared in Comparative Example 1.

[0070] Group C (MPS control group): Administered 0.3% MPS eye drops prepared in Comparative Example 2.

[0071] Group D (MPS+HA group): The 0.3% MPS / 0.2% HA compound eye drops prepared in Example 1 were administered.

[0072] 2. Modeling and Drug Administration: A dry eye model was successfully established by instilling 0.1% BAC solution into the rabbit eyes twice daily for 2 weeks. Drug administration was then initiated, with 50 μL administered four times daily for 4 weeks.

[0073] 3. Evaluation indicators and results were measured before treatment (week 0) and at 2 and 4 weeks after treatment.

[0074] Tear film breakup time (TBUT): Results are as follows: After 4 weeks of treatment, the average TBUT of groups B and C was prolonged by 2.5 seconds and 4.6 seconds, respectively; while the average TBUT of group D was prolonged by 7.8 seconds, significantly better than groups B and C (P < 0.01). Specific test data are shown in Table 5 and... Figure 1 .

[0075] Table 5: Statistical Comparison of Tear Film Breakup Time (TBUT)

[0076]

[0077]

[0078] Corneal fluorescein staining (CFS) scoring: The Oxford scoring system was used. Results are as follows: After 4 weeks of treatment, the average scores of groups B and C decreased by 1.8 and 2.4 points, respectively; while the average score of group D decreased by 4.5 points, showing significantly better improvement than groups B and C (PP < 0.01). In summary, the superior results of group D compared to the other two groups demonstrate that the combination of MPS and HA has a significant synergistic effect in the treatment of dry eye. Specific test data are shown in Table 6 and... Figure 2 .

[0079] Table 6: Statistical Comparison of Corneal Fluorescein Staining (CFS) Scores

[0080]

[0081] Histopathological examination: After treatment, corneal tissue was harvested for HE staining to observe the number of epithelial cell layers and goblet cell density. The results showed that group D had the most intact corneal epithelial structure, close to normal levels, and the goblet cell density recovery was also the most significant, superior to all control groups.

[0082] Test 2: Anti-inflammatory effect of 0.3% MPS / 0.2% HA compound eye drops

[0083] 1. Experimental model: Human corneal epithelial cells (HCEC) were used, and an inflammatory response was induced by lipopolysaccharide (LPS).

[0084] 2. Grouping:

[0085] control group

[0086] LPS model group (1 μg / mL LPS);

[0087] LPS + 0.2% HA group (Comparative Example 1);

[0088] LPS + 0.3% MPS group (Comparative Example 2);

[0089] LPS + 0.2% HA + 0.3% MPS group (Example 1).

[0090] Detection and Results: After 24 hours of culture, the concentrations of inflammatory factors IL-6 and TNF-α in the culture supernatant were detected by ELISA. The results are as follows: Compared with the LPS model group, the inhibition rates of IL-6 in the HA group and MPS group were 25% and 35%, respectively, while the inhibition rate in the HA+MPS group was as high as 78%. For TNF-α, the inhibition rates in the HA group and MPS group were 22% and 31%, respectively, while the inhibition rate in the HA+MPS group was as high as 71%. The inhibitory effects of both indicators were significantly greater than the simple additive effect of either agent, confirming the synergistic effect of anti-inflammatory activity. Specific test data are shown in Tables 7 and 8. Figure 3 , Figure 4 .

[0091] Table 7: Statistical comparison of IL-6 inhibition rates (%)

[0092]

[0093] Table 8: Statistical comparison of TNF-α inhibition rates (%)

[0094]

[0095] Test 3: The effect of 0.3% MPS / 0.2% HA compound eye drops on promoting corneal repair.

[0096] 1. Experimental model: A "scratch" was created on a fused HCEC monolayer using a sterile pipette tip.

[0097] 2. Grouping:

[0098] control group

[0099] LPS model group (1 μg / mL LPS);

[0100] LPS + 0.2% HA group (Comparative Example 1);

[0101] LPS + 0.3% MPS group (Comparative Example 2);

[0102] LPS + 0.2% HA + 0.3% MPS group (Example 1).

[0103] Detection and Results: The scratched area was photographed at 0 and 24 hours, and the healing rate was calculated. The results are as follows: After 24 hours, the healing rate was approximately 30% in the control group, approximately 35% in the HA group, and 50% in the MPS group. The healing rate in the HA+MPS group reached over 95%, almost completely healing. This indicates that the composition of this application also has a significant synergistic accelerating effect in promoting corneal epithelial cell migration and proliferation.

[0104] Test 4: Evaluation of ocular irritation of 0.3% MPS / 0.2% HA compound eye drops

[0105] The 0.3% MPS / 0.2% HA compound eye drops prepared in Example 1 were used to conduct an acute eye irritation test on six New Zealand white rabbits. Following the standard method in "Chemical Testing Methods", 0.1 mL of the solution was administered once into the conjunctival sac of the rabbit eye. The reactions of the cornea, iris, and conjunctiva were observed at 1, 24, 48, and 72 hours after administration.

[0106] Results: At all observation time points, all animals had corneal, iris, and conjunctival scores of 0, indicating no irritation. The mean score for acute eye irritation was 0, indicating no irritation. This suggests that the 0.3% MPS / 0.2% HA compound eye drops are highly safe and well-tolerated in rabbit eyes.

[0107] Test 5: Stability Study of 0.3% MPS / 0.2% HA Compound Eye Drops

[0108] The 0.3% MPS / 0.2% HA compound eye drops sample prepared in Example 1 was placed under accelerated stability test conditions (temperature 40℃±2℃, relative humidity 75%±5%) for 6 months. Test items included: appearance, pH value, osmolality, related substances, MPS content, HA content, and water loss rate. The test results are shown in Table 9.

[0109] Table 9

[0110]

[0111] Results analysis:

[0112] Appearance: Throughout the entire observation period, the solution remained a colorless and clear liquid, with no visible foreign matter.

[0113] pH value and osmotic pressure: No significant changes were observed within 6 months, and both remained within the range specified in the quality standard.

[0114] Active ingredient content: The content of MPS and HA remained above 98% of the initial content within 6 months, with minimal degradation.

[0115] Related substances: No significant increase was observed.

[0116] Water loss rate: Meets requirements.

[0117] Conclusion: The 0.3% MPS / 0.2% HA compound eye drops prepared in this application exhibit good physical and chemical stability under accelerated conditions, indicating that it has a shelf life of at least 24 months under normal conditions.

[0118] The above description is merely a preferred embodiment of this application and does not constitute any limitation on this application in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of this application, and these improvements and additions should also be considered within the scope of protection of this application. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of this application are equivalent embodiments of this application; furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of this application still fall within the scope of the technical solution of this application.

Claims

1. The use of an ophthalmic pharmaceutical composition comprising polysulfated mucopolysaccharide and sodium hyaluronate in the preparation of a drug for treating dry eye syndrome, characterized in that, The polysulfonic acid mucopolysaccharide has a weight percentage concentration of 0.1%-1.0%, and the sodium hyaluronate has a weight percentage concentration of 0.1%-0.5%.

2. The application according to claim 1, characterized in that, The polysulfated mucopolysaccharide has a weight percentage concentration of 0.3%, and the sodium hyaluronate has a weight percentage concentration of 0.2%.

3. The application according to claim 1, characterized in that, The weight ratio of the polysulfated mucopolysaccharide to sodium hyaluronate is 1:(0.5-1).

4. The application according to claim 1, characterized in that, The composition can prolong tear film breakup time in a rabbit model of dry eye and reduce corneal fluorescein staining score.

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