CN115040535B - Application of sulfated hyaluronic acid in preparing eye drops for preventing corneal fibrosis and corneal scar - Google Patents

Abstract

The invention discloses the application of sulfated hyaluronic acid in preparing eye drops for preventing corneal fibrosis and corneal scar. The eye drops contain sulfated hyaluronic acid, a pH adjuster and an osmotic pressure adjuster. Sulfated hyaluronic acid, the main component of the eye drops, can form a uniform, complete and stable coating on the surface of the corneal stroma, which stays in the eye for a long time and has high bioavailability. The coating can effectively prevent the over-secreted cytokines from infiltrating the stroma layer to promote epithelial healing, prevent them from inducing the differentiation of corneal stromal cells and corneal fibroblasts, and prevent corneal fibrosis and corneal scar formation. The eye drop has simple preparation process, stable quality and definite curative effect, can play an excellent preventive effect on common ophthalmic complications such as corneal fibrosis and corneal scar, and has good clinical application prospect.

Description

Sulfated hyaluronic acid in the preparation of eye drops for preventing corneal fibrosis and corneal scar Applications

technical field

The invention belongs to the field of eye drops, and in particular relates to the application of sulfated hyaluronic acid in preparing eye drops for preventing corneal fibrosis and corneal scar.

Background technique

Corneal fibrosis and corneal scarring are common complications of corneal damage and corneal surgery. The main symptoms are that normal corneal tissue is replaced by fibrotic tissue (disorganized extracellular matrix), which further affects the patient's cornea. Transparency and vision. At present, studies on the pathogenesis of corneal fibrosis and scar have shown that the main reason for its occurrence is partial corneal epithelial tissue defects caused by corneal surgery and mechanical damage to the cornea. In order to speed up the repair of corneal epithelial tissue defects and maintain the integrity of corneal structure, corneal epithelial cells around the defect secrete a large number of cytokines (mainly transforming growth factor β1, platelet-derived growth factor, etc.) to promote corneal re-epithelialization. These excessively secreted cytokines will penetrate the damaged corneal basement membrane and Bowman's membrane into the stroma, and induce normal corneal stromal cells and corneal fibroblasts to differentiate and proliferate into myofibroblasts. The differentiated myofibroblasts secrete disordered and disordered extracellular matrix to the surroundings, eventually leading to corneal fibrosis and corneal scarring. Corneal fibrosis and corneal scarring are the main causes of corneal blindness worldwide.

In clinical practice, the prevention of corneal fibrosis and corneal scar is mainly controlled by using mitomycin C or hormone eye drops (such as: tobramycin dexamethasone eye drops, etc.). Although such drug eye drops have been widely used, there are inherent limitations. Eye drops have high ocular clearance and short residence time, resulting in low bioavailability of such eye drops. Secondly, mitomycin C is a cell division inhibitor, which inhibits corneal fibrosis and corneal scar mainly by preventing excessive proliferation of corneal cells caused by oversecreted cytokines. Side effects such as increased intraocular pressure may occur during the application of this drug, resulting in limited application.

Contents of the invention

The purpose of the present invention is to provide the application of sulfated hyaluronic acid in the preparation of eye drops for preventing corneal fibrosis and corneal scar. The eye drops contain sulfated hyaluronic acid, which can effectively prevent corneal fibrosis and corneal scarring.

The purpose of the present invention is achieved through the following technical solutions.

Application of the sulfated hyaluronic acid in the preparation of eye drops for preventing corneal fibrosis and corneal scar, the eye drops comprising sulfated hyaluronic acid, a pH regulator and an osmotic pressure regulator.

Preferably, the concentration of the sulfated hyaluronic acid in the eye drops is 0.5-5 mg/ml. More preferably, the concentration of the sulfated hyaluronic acid in the eye drops is 1.0-2.0 mg/ml, most preferably 1.0 mg/ml.

Preferably, the molecular weight of the sulfated hyaluronic acid is 1-10 million Daltons. More preferably, the molecular weight of the sulfated hyaluronic acid is 1 to 1.5 million Daltons.

Preferably, the sulfation degree of the sulfated hyaluronic acid is 1.0-3.0. More preferably, the degree of sulfation of the sulfated hyaluronic acid is 2.5-3.0, most preferably 2.6.

Preferably, the sulfated hyaluronic acid includes, but is not limited to, metal salts such as sulfated hyaluronic acid, sulfated hyaluronic acid sodium salt, and sulfated hyaluronic acid potassium salt.

Preferably, the metal salt of sulfated hyaluronic acid is sodium sulfated hyaluronic acid or potassium sulfated hyaluronic acid.

Preferably, the osmotic pressure regulator includes but not limited to sugar isotonic agents such as 5% glucose aqueous solution, salt isotonic agents such as 0.9% sodium chloride solution, organic isotonic agents such as glycerin and the like.

Preferably, the pH regulator includes but not limited to phosphate buffer, borate buffer, citrate buffer, acetate buffer, tartrate buffer, carbonate buffer, amino acid buffer Wait.

Preferably, a solution system composed of at least one of bacteriostat, stabilizer, thickener, solubilizer and protein protectant can also be added to the eye drop. Furthermore, drugs including but not limited to tobramycin and dexamethasone can be added to the eye drop system to prepare the eye drops with multiple functions of preventing corneal fibrosis, corneal scarring, anti-inflammation, and anti-infection. eye drops.

Preferably, the dosage form of the eye drops can be aqueous solution, suspension, emulsion and the like. More preferably, the eye drops are provided as an aqueous solution.

Preferably, the preparation of the eye drops comprises the following steps:

Dissolve sulfated hyaluronic acid in physiological saline as an osmotic pressure regulator, add a pH regulator, stir and dissolve in the solution, adjust the pH to 7.0~7.5, sterilize, and dispense.

Preferably, the sterilization method is one of filtration membrane sterilization, radiation sterilization and high temperature and high pressure sterilization.

The principle of the present invention is that after the eye drops are dropped onto the ocular surface, the sulfated hyaluronic acid can quickly form a uniform, complete and stable coating on the damaged ocular surface corneal stroma. The coating has high biological activity and can combine with oversecreted cytokines (transforming growth factor β1, platelet-derived growth factor, etc.) to prevent them from entering the corneal stroma in large quantities to induce downstream reactions, and to achieve anti-inflammatory effects on corneal fibrosis and corneal scarring. effective prevention.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The eye drops of the present invention contain sulfated hyaluronic acid. Compared with the existing drug eye drops, it can quickly form a uniform, complete and stable coating on the damaged corneal stroma, and the residence time on the ocular surface Long, high bioavailability.

(2) The preparation process of the eye drops of the present invention is simple, repeatable and stable, and has definite curative effect.

(3) The eye drops of the present invention can have an excellent preventive effect on common complications such as corneal fibrosis and corneal scar, and has important scientific research significance and good clinical application prospects.

Description of drawings

Fig. 1 is a principle diagram of the application of the eye drops for preventing corneal fibrosis and corneal scar of the present invention.

Fig. 2 is the high-resolution spectrum of sulfur element 2p orbital by X-ray photoelectron spectroscopy of rabbit corneal stroma with sulfated hyaluronic acid coating obtained in Example 5.

Fig. 3 is the high-resolution spectrum of sulfur element 2p orbital by X-ray photoelectron spectroscopy of rabbit corneal stroma with sulfated hyaluronic acid coating obtained in Example 7.

Fig. 4 is the high-resolution spectrum of the 2p orbital of sulfur element obtained in Example 8 with the sulfated hyaluronic acid coating rabbit corneal stroma X-ray photoelectron spectroscopy.

Fig. 5 is a graph showing the experimental results of CCK8 proliferation of corneal epithelial cells obtained in Example 9 on type I collagen membrane coated with sulfated hyaluronic acid.

Fig. 6 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings obtained in Example 10.

Fig. 7 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings obtained in Example 11.

Fig. 8 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings obtained in Example 12.

Fig. 9 is a diagram showing the observation results of corneal slit lamp bright field 28 days after the curative effect experiment of the rabbit corneal fibrosis model in Example 13.

Fig. 10 is the observation result of corneal optical coherence tomography 28 days after the curative effect experiment of the rabbit corneal fibrosis model in Example 13.

Fig. 11 is an immunohistochemical staining diagram of corneal α-smooth actin 28 days after the curative effect experiment of the rabbit corneal fibrosis model in Example 13.

detailed description

The technical solutions of the present invention will be further described below in conjunction with the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

The principle diagram of the application of the eye drops for preventing corneal fibrosis and corneal scar of the present invention is shown in FIG. 1 .

Example 1

Dissolve 50.0 mg of sulfated hyaluronic acid (molecular weight 1 to 1.5 million Daltons, degree of sulfation: 2.6) in 50 ml of normal saline, then add 0.1 g of sodium dihydrogen phosphate and stir to dissolve. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0-7.5, filter and sterilize, and dispense to obtain sulfated hyaluronic acid eye drops with a concentration of 1.0 mg/ml.

Example 2

Dissolve 250.0 mg of sulfated hyaluronic acid (molecular weight 1 to 1.5 million Daltons, degree of sulfation: 2.6) in 50 ml of normal saline, then add 0.1 g of sodium dihydrogen phosphate and stir to dissolve. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0-7.5, filter and sterilize, and dispense to obtain sulfated hyaluronic acid eye drops with a concentration of 5.0 mg/ml.

Example 3

Dissolve 25.0 mg of sulfated hyaluronic acid (molecular weight 1 to 1.5 million Daltons, degree of sulfation: 2.6) in 50 ml of normal saline, then add 0.1 g of sodium dihydrogen phosphate and stir to dissolve. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0-7.5, filter and sterilize, and dispense to obtain sulfated hyaluronic acid eye drops with a concentration of 0.5 mg/ml.

Example 4

Dissolve 50.0 mg of sulfated hyaluronic acid (molecular weight 1 to 1.5 million Daltons, degree of sulfation: 2.6) in 50 ml of normal saline, then add 10 μg of benzalkonium chloride (bacteriostatic agent), 0.1 g of diphosphate Sodium hydrogen is fully stirred to dissolve. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0-7.5, filter and sterilize, and dispense to obtain 1.0 mg/ml sulfated hyaluronic acid eye drops containing 3.0 mg/ml tobramycin.

Example 5

Take fresh rabbit corneal tissue, remove the corneal epithelium, Bowman's membrane, Bowman's membrane and endothelium, and use the remaining corneal stroma to simulate the exposed corneal stroma surface after corneal surgery or mechanical damage.

The eye drops prepared in Example 1 were dripped onto the surface of the rabbit corneal stroma and stayed for 30 seconds, rinsed with distilled water and then air-dried. The change of sulfur element was analyzed by X-ray photoelectron spectroscopy on the obtained corneal stroma surface. Fig. 2 is a high-resolution spectrum of sulfur element 2p orbital by X-ray photoelectron spectroscopy of rabbit corneal stroma coated with sulfated hyaluronic acid. The results showed that the sulfur 2p peak corresponding to the sulfate group appeared in the high-resolution spectrum of the sulfur 2p on the substrate surface with the coating, indicating the successful formation of the sulfated hyaluronic acid coating.

Example 6 Visualization of Sulfated Hyaluronic Acid Coating Formation Process

In order to realize the visualization of the sulfated hyaluronic acid coating, a trace amount of 6-aminofluorescein was grafted onto the sulfated hyaluronic acid, and the specific operation was as follows: take 100.0 mg of sulfated hyaluronic acid (molecular weight: 100-1.5 million dal 10.0 mg 6-aminofluorescein (the solubility of 6-aminofluorescein is low in water, and there should be a small amount of undissolved 6-aminofluorescein in the solution system at this time) in 50 ml of normal saline. aminofluorescein). After thorough stirring, 69.4 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide was added into the solution and reacted for 24 hours. After the reaction was completed, the insoluble matter was removed by centrifugation, and the remaining liquid was dialyzed in distilled water for 72 hours in a dialysis bag with a molecular weight cut off of 3000, and then freeze-dried for use. The whole process of grafting reaction and dialysis was carried out in the dark.

Take 50.0 mg of the prepared 6-aminofluorescein grafted sulfated hyaluronic acid and dissolve it in 50 ml of normal saline, add 0.1 g of sodium dihydrogen phosphate into the solution and stir well to dissolve. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0~7.5, filter and sterilize, and pack in aliquots.

The obtained eye drops are added dropwise to the surface of the corneal stroma of the rabbit, and the formation process of the sulfated hyaluronic acid coating on the surface of the corneal stroma is observed through a laser confocal microscope. The results show that sulfated hyaluronic acid can form a uniform and complete coating on the corneal stroma surface within 30 seconds after being dropped on it. The situation of the sulfated hyaluronic acid coating formed after soaking for 30 minutes is consistent with that of the coating formed after soaking for 30 seconds, indicating that the coating is very stable under eye flushing conditions, has a long residence time and high bioavailability.

Example 7

Take fresh rabbit corneal tissue, remove the corneal epithelium, Bowman's membrane, Bowman's membrane and endothelium, and use the remaining corneal stroma to simulate the exposed corneal stroma surface after corneal surgery or mechanical damage.

The eye drops prepared in Example 2 were dripped onto the surface of the rabbit corneal stroma and stayed for 30 seconds, rinsed with distilled water and then air-dried. The change of sulfur element was analyzed by X-ray photoelectron spectroscopy on the obtained corneal stroma surface.

Take 250.0 mg of the 6-aminofluorescein grafted sulfated hyaluronic acid prepared in Example 6 and dissolve it in 50 ml of physiological saline, add 0.1 g of sodium dihydrogen phosphate into the solution and stir to dissolve fully. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0~7.5, filter and sterilize, and pack in aliquots. The resulting eye drops with a concentration of 5.0 mg/ml were added dropwise to the surface of the corneal stroma of the rabbit for 30 seconds, rinsed, and the formation of the sulfated hyaluronic acid coating on the surface of the corneal stroma was observed by confocal laser microscopy.

Figure 3 is the high-resolution spectrum of the sulfur 2p orbital of the sulfated hyaluronic acid-coated rabbit corneal stroma by X-ray photoelectron spectroscopy when the concentration of the sulfated hyaluronic acid component in the eye drops is 5.0 mg/ml. The results showed that the sulfur 2p peak corresponding to the sulfate group appeared in the high-resolution spectrum of the sulfur 2p on the surface of the substrate, indicating the successful formation of the sulfated hyaluronic acid coating.

At the same time, the formation of the coating was observed by laser confocal microscopy. When the concentration of the sulfated hyaluronic acid component in the eye drops was 5.0 mg/ml, the sulfated hyaluronic acid could be dropped on the surface of the corneal stroma within 30 seconds. Form a uniform and complete coating on it.

Example 8

Take fresh rabbit corneal tissue, remove the corneal epithelium, Bowman's membrane, Bowman's membrane and endothelium, and use the remaining corneal stroma to simulate the exposed corneal stroma surface after corneal surgery or mechanical damage.

The eye drops prepared in Example 3 were dripped onto the surface of the rabbit corneal stroma and stayed for 30 seconds, rinsed with distilled water and then air-dried. The change of sulfur element was analyzed by X-ray photoelectron spectroscopy on the obtained corneal stroma surface.

25.0 mg of 6-aminofluorescein grafted sulfated hyaluronic acid obtained in Example 6 was dissolved in 50 ml of normal saline, and 0.1 g of sodium dihydrogen phosphate was added to the solution, stirred and dissolved fully. Use an appropriate amount of sodium hydroxide to adjust the pH to 7.0~7.5, filter and sterilize, and pack in aliquots. The resulting eye drops with a concentration of 0.5 mg/ml were added dropwise to the surface of the corneal stroma of the rabbit for 30 seconds, rinsed, and the formation of the sulfated hyaluronic acid coating on the surface of the corneal stroma was observed through a laser confocal microscope.

Fig. 4 is the high-resolution spectrum of the sulfur 2p orbital of the sulfated hyaluronic acid-coated rabbit corneal stroma X-ray photoelectron spectroscopy when the concentration of the sulfated hyaluronic acid component in the eye drops is 0.5 mg/ml. The results showed that the sulfur 2p peak corresponding to the sulfate group appeared in the high-resolution spectrum of the sulfur 2p on the surface of the substrate, indicating the successful formation of the sulfated hyaluronic acid coating.

At the same time, the formation of the coating was observed by laser confocal microscope. When the concentration of the sulfated hyaluronic acid component in the eye drops was 0.5 mg/ml, the sulfated hyaluronic acid could be dropped on the surface of the corneal stroma within 30 seconds. Form a uniform and complete coating on it.

Example 9 Biological Safety of Sulfated Hyaluronic Acid Coating

Soak a sterile circular type I collagen membrane with a diameter of 1 cm in 10 ml of the eye drops prepared in Example 1 for 5 minutes, rinse with PBS to obtain a type I collagen membrane with a sulfated hyaluronic acid coating . Corneal epithelial cells were seeded on it at a seeding density of 10,000 cells/cm ² and cultured at 37 °C under 5% CO ₂ . CCK8 experiments were carried out at 24 hours, 48 hours and 72 hours of culture respectively. Figure 5 is the results of CCK8 proliferation of corneal epithelial cells on type I collagen membrane coated with sulfated hyaluronic acid. The results showed that corneal epithelial cells could proliferate normally on the type I collagen membrane coated with sulfated hyaluronic acid, and the proliferation rate was not significantly different from that of the control group, which proved that the sulfated hyaluronic acid coating had good biocompatibility.

Example 10 When the concentration of the sulfated hyaluronic acid component in the eye drops is 1.0 mg/ml, the barrier effect of the formed sulfated hyaluronic acid coating on the penetration of TGF-β1 (transforming growth factor β1)

The rabbit corneal stroma with sulfated hyaluronic acid coating prepared in Example 5 was immersed in 5 ml of PBS solution containing 30 ng/ml TGF-β1 for 1 hour. After immersion, the remaining TGF-β1 on the surface was washed away with PBS, and 30 microns of corneal stroma on the surface were removed with surgical instruments. The TGF-β1 content in the obtained tissue was determined after homogenization. Uncoated rabbit corneal stroma was subjected to the same operation as a control experiment. Fig. 6 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings. The results showed that compared with the uncoated group, the content of TGF-β1 in the corneal stroma of the sulfated hyaluronic acid coating group was significantly reduced, indicating that the sulfated hyaluronic acid coating can effectively prevent TGF-β1 from penetrating into the corneal stroma.

Example 11 When the concentration of the sulfated hyaluronic acid component in the eye drops is 5.0 mg/ml, the barrier effect of the formed sulfated hyaluronic acid coating on the penetration of TGF-β1 (transforming growth factor β1)

The rabbit corneal stroma with sulfated hyaluronic acid coating prepared in Example 7 was immersed in 5 ml of PBS solution containing 30 ng/ml TGF-β1 for 1 hour. After immersion, the remaining TGF-β1 on the surface was washed away with PBS, and 30 microns of corneal stroma on the surface were removed with surgical instruments. The TGF-β1 content in the obtained tissue was determined after homogenization. Uncoated rabbit corneal stroma was subjected to the same operation as a control experiment. Fig. 7 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings. The results showed that compared with the uncoated group, the content of TGF-β1 in the corneal stroma of the sulfated hyaluronic acid coating group was significantly reduced, indicating that the sulfated hyaluronic acid coating can effectively prevent TGF-β1 from penetrating into the corneal stroma.

Example 12 When the concentration of the sulfated hyaluronic acid component in the eye drops is 0.5 mg/ml, the barrier effect of the formed sulfated hyaluronic acid coating on the penetration of TGF-β1 (transforming growth factor β1)

The rabbit corneal stroma with sulfated hyaluronic acid coating prepared in Example 8 was immersed in 5 ml of PBS solution containing 30 ng/ml TGF-β1 for 1 hour. After immersion, the remaining TGF-β1 on the surface was washed away with PBS, and 30 microns of corneal stroma on the surface were removed with surgical instruments. The TGF-β1 content in the obtained tissue was determined after homogenization. Uncoated rabbit corneal stroma was subjected to the same operation as a control experiment. Fig. 8 is a graph showing the content of TGF-β1 in rabbit corneal stroma with different coatings. The results showed that compared with the uncoated group, the content of TGF-β1 in the corneal stroma of the sulfated hyaluronic acid coating group was significantly reduced, indicating that the sulfated hyaluronic acid coating can effectively prevent TGF-β1 from penetrating into the corneal stroma.

Example 13 Curative Effect Experiment of Rabbit Corneal Fibrosis Model

Rabbit corneal fibrosis model establishment: New Zealand rabbits were anesthetized, the conjunctival sac was flushed and eye anesthesia eye drops were instilled. Use a 5.0 mm corneal trephine to position in the center of the cornea and rotate slightly to cut the corneal tissue. About 100 μm of corneal tissue was surgically removed, and the cutting thickness was determined by corneal A-ultrasound pachymeter.

Experimental grouping: This experiment is divided into three groups: the control group, the experimental group, and the comparison group.

Therapeutic method: control group - drop tobramycin eye drops to prevent infection; experimental group - drop tobramycin to prevent infection, drop the eye drops prepared in Example 1; contrast group - drop tobramycin Dexamethasone eye drops for prevention and treatment of infection (comparison of clinical medication). Eye drops 4 times a day, 10 minutes between different eye drops.

The occurrence of corneal fibrosis and corneal scar was observed by photographing with slit lamp. The results are shown in Figure 9. After 28 days of medication, the experimental group that used the sulfated hyaluronic acid eye drops had less corneal fibrosis and scarring than the other groups. From the results of optical coherence tomography (see Figure 10), it can be seen that the highly reflective white bands in the experimental group were the slightest, indicating that the new corneal stroma in this group was more regular than the other two groups. At the same time, immunohistochemical staining was carried out on the corneal fibrosis marker protein α-smooth actin (see Figure 11), and the expression range of the protein in the experimental group was significantly lower than that in the other two groups. The above observation results all show that the eye drops of the present invention can effectively prevent corneal fibrosis and corneal scarring.

Matters not covered in the present invention are known technologies.

The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention shall fall within the protection scope of the present invention.

Claims (8)

1. The application of sulfated hyaluronic acid in preparing eye drops for preventing corneal fibrosis and corneal scar is characterized in that the eye drops comprise sulfated hyaluronic acid, a pH regulator and an osmotic pressure regulator;

after the eye drops are dripped on the ocular surface, the sulfated hyaluronic acid in the eye drops forms a uniform, complete and stable coating on the damaged corneal stroma on the ocular surface;

the molecular weight of the sulfated hyaluronic acid is 100 to 150 kilodaltons, and the sulfation degree is 2.6.

2. The use of the sulfated hyaluronic acid as claimed in claim 1, in the preparation of eye drops for preventing corneal fibrosis and corneal scar, wherein the concentration of the sulfated hyaluronic acid in the eye drops is 0.5 to 5.0 mg/ml.

3. The use of the sulfated hyaluronic acid as defined in claim 2, in the preparation of eye drops for preventing corneal fibrosis and corneal scar, wherein the concentration of the sulfated hyaluronic acid in the eye drops is 1.0 to 2.0 mg/ml.

4. Use of sulfated hyaluronic acid as defined in any of claims 1 to 3, in the preparation of eye drops for the prevention of corneal fibrosis and corneal scarring, wherein the sulfated hyaluronic acid comprises sulfated hyaluronic acid and metal salts thereof.

5. The use of sulfated hyaluronic acid as defined in claim 4, for the preparation of eye drops for the prevention of corneal fibrosis and corneal scarring, wherein the metal salt of sulfated hyaluronic acid is a sodium or potassium salt of sulfated hyaluronic acid.

6. Use of sulfated hyaluronic acid as defined in any of claims 1-3, in the preparation of ophthalmic solutions for the prevention of corneal fibrosis, corneal scarring, wherein the osmolality adjusting agent is at least one of an aqueous glucose solution, a sodium chloride solution and glycerol; the pH regulator is at least one of phosphate buffer solution, borate buffer solution, citrate buffer solution, acetate buffer solution, tartrate buffer solution, carbonate buffer solution and amino acid buffer solution.

7. The use of sulfated hyaluronic acid as claimed in any of claims 1 to 3, for the preparation of eye drops for the prevention of corneal fibrosis and corneal scarring, wherein a solution system consisting of at least one of a bacteriostatic agent, a stabilizer, a viscosity-increasing agent, a solubilizing agent and a protein protectant is further added to the eye drops; the dosage form of the eye drops is aqueous solution, suspension or emulsion.

8. Use of sulfated hyaluronic acid according to any of claims 1 to 3, for the preparation of ophthalmic solutions for the prevention of corneal fibrosis, corneal scarring, characterized in that the preparation of said ophthalmic solutions comprises the following steps:

dissolving sulfated hyaluronic acid in physiological saline as an osmotic pressure regulator, adding a pH regulator into the solution, fully stirring and dissolving, regulating the pH to 7.0 to 7.5, sterilizing and packaging.

Images