Diquafosol sodium composition, eye drops and preparation methods of diquafosol sodium composition and eye drops

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ophthalmic pharmaceutical composition of diquafosol sodium, eye drops of the ophthalmic pharmaceutical composition and corresponding preparation methods of the ophthalmic pharmaceutical composition and the eye drops. The pharmaceutical composition is mainly prepared from diquafosol sodium and sodium hyaluronate, and in terms of W / V, the dosage of diquafosol sodium is 1%-5%, and the dosage of sodium hyaluronate is 0.01%-0.1%. The diquafosol sodium and the sodium hyaluronate are prepared into the pharmaceutical composition, the sodium hyaluronate serves as a tackifier, the effects of thickening, tackifying, water retention and wetting are achieved, the biological adhesiveness of the eye drops can be improved, the retention time of the medicine in eyes is prolonged as much as possible, the medicine administration frequency is remarkably reduced through the composition, the compliance of a patient is improved, and the curative effect is good. The irritation risk and side effects caused by frequent and long-term use of diquafosol sodium are avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a diquafosol sodium composition and eye drops thereof, as well as a corresponding preparation method. Background Art

[0002] Dry eye is caused by insufficient tear secretion, excessive evaporation or abnormal tear components, which leads to eye discomfort and visual dysfunction. Since many patients with dry eye do not know how to take care of their eyes, the lesions often develop faster and worsen. In addition, since ophthalmologists in primary hospitals lack sufficient knowledge of this disease, such patients are often misdiagnosed. They cannot receive timely and correct diagnosis and treatment, and may even be given the wrong treatment. Dry eye is a chronic disease that requires long-term treatment. The main treatment drug is artificial tears.

[0003] Diquafosol Sodium is a P2Y2 receptor agonist, the drug molecular formula: C 18 H 22 N4Na4O 23 P4, molecular weight: 878.23, chemical name: P1, P4-bis(5'-uridine)tetrasodium tetraphosphate (IUPAC). The chemical structure of the drug is as follows:

[0004] This drug is a preparation containing diquafosol sodium, a P2Y2 receptor agonist developed by Inspire Corporation of the United States. P2Y2 receptors are known to be located in the eyelid / conjunctival epithelium (including goblet cells) and meibomian glands (fat cells and ductal epithelial cells) in the ocular surface tissue 1), ATP (adenosine triphosphate) or UTP (uridine triphosphate) It is reported that it acts on this P2Y2 receptor and promotes the secretion of water and mucin in the conjunctiva. Diquafosol sodium is a dinucleotide derivative that is more stable than ATP and UTP in aqueous solution and is therefore suitable for formulation as an aqueous eye drop, and it has been confirmed from nonclinical studies that it has a new mechanism of action that promotes the secretion of tears containing mucin in the conjunctiva and improves tears from qualitative and quantitative aspects, and is expected to be effective as a therapeutic agent for dry eye disease. In this context, Santen Pharmaceutical Co., Ltd. introduced diquafosol sodium from Inspire and conducted clinical trials on dry eye patients in Japan. In a phase III study, the drug (3% diquafosol sodium ophthalmic solution) was used to improve the efficacy and safety of corneal epithelial damage, fluorescein staining scores, and corneal and conjunctival epithelial damage as an indicator of improved Bengal rose staining scores. The drug's efficacy and safety were confirmed in a 52-week eye drop study, and it was approved for production and sale as an eye drop for the treatment of dry eye in April 2010. Its clinical use is 1 drop in each eye, 6 times a day. Diquafosol sodium eye drops are used many times a day and are used frequently, which brings inconvenience to patients and affects their compliance with medication. In clinical trials, all adverse reactions were found to be local ocular adverse reactions. The main adverse reactions were eye secretions, eye irritation, eye itching, eye congestion, eye pain, etc. In addition, since dry eye is a chronic disease that requires long-term treatment, long-term and frequent use of diquafosol sodium eye drops may cause instability in the internal environment of the eye and cause eye inflammation, etc. Therefore, there is an urgent need to solve the problem of diquafosol sodium eye drops that can effectively prevent and treat dry eyes while reducing the frequency of use by patients and avoiding side effects caused by long-term use of diquafosol sodium.

[0005] Sodium hyaluronate, also known as sodium hyaluronate, is an acidic mucopolysaccharide that was first isolated from the vitreous body of bovine eyes. Sodium hyaluronate is widely distributed in the extracellular matrix of connective tissues of animals and humans. With its unique molecular structure and physical and chemical properties, it exhibits a variety of important physiological functions in the body, such as lubricating joints, regulating the permeability of blood vessel walls, regulating the diffusion and movement of proteins, water and electrolytes, and promoting wound healing. More importantly, sodium hyaluronate has a special water-retaining effect and is the best moisturizing substance found in nature so far. It is called an ideal natural moisturizing factor. Hyaluronic acid is a substance with a chemical structure, molecular weight and rheological properties similar to mucin (a tear component). Due to its viscoelasticity, the eyes can remain lubricated without causing visual impairment. Sodium hyaluronate eye drops have the following effects: (1) It binds to fibronectin in the corneal stroma to promote the connection and extension of corneal epithelial cells, thereby accelerating corneal epithelial repair and shortening wound healing time; (2) It has excellent water retention, prevents corneal drying, and promotes corneal epithelial cell proliferation; (3) Sodium hyaluronate is an important component of the corneal stroma, so it plays an important role in corneal cell growth and development, inflammation and wound healing. In addition, sodium hyaluronate eye drops have no systemic effects except for the basic local physical effects (surface wetting effect), and there are no drug interactions except for the known effects of topical eye drops. After local application to the eye, sodium hyaluronate is not absorbed, and there is no evidence that sodium hyaluronate can penetrate the cornea. Even if it is injected into the anterior chamber of the eye, there is only a negligible concentration in the blood vessels and it is quickly metabolized by the liver, so there is no systemic toxic reaction. Therefore, sodium hyaluronate solution is a perfect ophthalmic drug carrier.

[0006] Santen Pharmaceutical Co., Ltd. has launched Hyalein, a sodium hyaluronate eye drop. ® , the indications are corneal epithelial damage caused by external factors such as Sjögren's syndrome, Stevens-Johnson syndrome, dry eye syndrome, and wearing contact lenses. The literature points out that there are two specifications, 0.1% and 0.3%, respectively. Usage and dosage: generally 1 drop once, 5 to 6 times a day, which can be increased or decreased appropriately according to symptoms. Generally, 0.1% sodium hyaluronate eye drops are used, and 0.3% sodium hyaluronate eye drops are used for severe diseases and when the effect is not obvious.

[0007] The prescription composition of 3% diquafosol sodium eye drops is diquafosol sodium, benzalkonium chloride, disodium hydrogen phosphate, sodium chloride, potassium chloride, sodium hydroxide, hydrochloric acid and water for injection; its clinical usage is 1 drop in each eye each time, 6 times a day. It has low bioavailability, is used very frequently, and has poor patient compliance.

[0008] Since both diquafosol sodium and sodium hyaluronate have eye drop products used by patients with dry eye disease, they both play an important role in the treatment of dry eye disease. However, according to the usage and dosage of the eye drops of the two, patients use them many times a day and use them frequently, which brings inconvenience to patients. Summary of the invention

[0009] The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and invent an ophthalmic composition of diquafosol sodium and its eye drops, aiming to prolong the residence time of the drug in the eye, improve the moisturizing effect on the eye, thereby facilitating the drug to exert its therapeutic effect, reduce the number of administrations of diquafosol sodium, stabilize the local drug concentration of diquafosol sodium in the eye, reduce side effects, and improve patient compliance.

[0010] To achieve the above object, the scheme adopted by the present invention is: The invention discloses an ophthalmic composition of diquafosol sodium. The pharmaceutical composition consists of diquafosol sodium and sodium hyaluronate. In terms of W / V, the dosage of diquafosol sodium is 1%-5%, and the dosage of sodium hyaluronate is 0.01%-0.1%.

[0011] In solution-type eye drops, the solution has a certain viscosity, which will increase the time the drug solution stays in the eye, which is more conducive to the absorption of the drug in the eye and has better bioavailability of the drug. The inventor prepared diquafosol sodium and sodium hyaluronate into a composite according to different proportions, and evaluated the effect of the drug's residence time in the eye by indicators such as kinematic viscosity. After a large number of experiments, it was found that adding sodium hyaluronate to diquafosol sodium eye drops can give the drug a certain range of viscosity, thereby prolonging the drug's eye residence time and assisting the drug to be better absorbed; the inventor used a dialysis bag to simulate the cornea, and used a fluorescent labeling method to drip fluorescent material particles into diquafosol sodium ophthalmic preparations of different viscosities, dripped them on the surface of the dialysis membrane, observed the fluorescence through the membrane at different times, and inferred the preparation's residence time in the human eye based on the fluorescence retention time. The results showed that the viscosity was between 3 and 7 mm. 2 / s, the fluorescence retention time is the longest, and the viscosity is too high (greater than 7 mm 2 / s), the fluorescent substance is difficult to penetrate, indicating that it may affect drug absorption, and the viscosity is too small (<3mm 2 / s), the fluorescent substance will penetrate faster and cannot prolong the drug's residence time in the eye. According to an embodiment of the present invention, the inventor experimentally determined the kinematic viscosity of the composition of diquafosol sodium and sodium hyaluronate at different concentrations, preferably the amount of diquafosol sodium is 2.5%, and the amount of sodium hyaluronate is 0.05%.

[0012] Kinematic viscosity test method: Take 10 ml of the test sample, and according to the regulations under each item of the product, take an appropriate Pinnacle capillary viscometer, connect a rubber tube to branch tube F, block tube port 2 with a finger, invert the viscometer, insert tube port 1 into the test sample (or test solution, the same below), and draw air from the other end of the rubber tube so that the test sample fills balls C and A and reaches the determination line m2. Take out the viscometer and quickly turn it upside down, wipe off the test sample adhering to the outside of the tube, remove the rubber tube and connect it to tube port 1, fix the viscometer vertically in a constant temperature water bath, and make the liquid level of the water bath higher than the middle of ball C. After leaving it for 15 minutes, draw air from the other end of the rubber tube so that the test sample fills ball A and exceeds the determination line m1, open the rubber tube port, and let the test sample fall naturally in the tube. Use a stopwatch to accurately record the outflow time for the liquid level to drop from the determination line m1 to the determination line m2. Without reloading the sample, repeat the measurement three times according to the law. The difference between each measurement value and the average value shall not exceed ±0.25% of the average value. Take another sample for the same operation. The total average value of the two consecutive samples is calculated as follows, which is the kinematic viscosity of the sample. The results are shown in Table 1: Kinematic viscosity calculation formula: υ = Kt Wherein kinematic viscosity is υ, mm 2 / s Where K is the viscometer constant measured by a standard solution of known viscosity, mm 2 / s 2 t is the measured average outflow time, s.

[0013] Table 1 Prescription information of the combination of sodium hyaluronate and diquafosol sodium at different concentrations

[0014] Furthermore, in the present invention, the pharmaceutical composition can be prepared into a solution-type eye drop by adding any one or more of the pharmaceutical excipients such as a buffer, an osmotic pressure regulator, a pH regulator and water for injection; Preferably, the pharmaceutical excipients that can be added are selected from anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride, sodium hydroxide, hydrochloric acid and water for injection.

[0015] Furthermore, the pharmaceutical excipients that can be added may also include disodium edetate, aminocaproic acid, benzalkonium chloride, etc.

[0016] The present invention also discloses a method for preparing the above-mentioned diquafosol sodium ophthalmic composition, which specifically comprises: (1) Weigh sodium chloride, potassium chloride, and anhydrous disodium hydrogen phosphate and add them in sequence into a preparation cup containing 10% of the total amount of water for injection, and stir to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the prescribed amount of sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, control the temperature of the dissolution process at 60±5°C, and cool to room temperature after complete dissolution; (4) Weigh diquafosol sodium and add 30% of the total amount of water for injection to dissolve at room temperature; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution to 7.0±0.2 using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid according to the specific situation; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) Filter the solution obtained in step (7) once through a 0.45 μm microporous filter membrane in a dust flow vehicle simulating a Class B production environment; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust flow vehicle simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain the finished product.

[0017] According to an embodiment of the present invention, in the sodium diquafosol-sodium hyaluronate ophthalmic pharmaceutical composition, by adding auxiliary material buffer anhydrous disodium hydrogen phosphate, osmotic pressure regulators sodium chloride, potassium chloride, pH regulator sodium hydroxide and hydrochloric acid, the eye drops have a pH value and osmotic pressure that are more suitable for eye use, and at the same time stabilize the viscosity of the sodium diquafosol solution to ensure the local stability of the solution in the eye, and the product quality is not lower than that of existing commercially available preparations.

[0018] The inventors used a dialysis bag to simulate the cornea, and adopted the fluorescent labeling method to simulate the eye drops prepared by the pharmaceutical composition of diquafosol sodium in the present invention under different dosing times, and measured the fluorescence amount through the membrane by observing the commercially available sodium hyaluronate eye drops and diquafosol sodium eye drops. ® The fluorescence amount under the dosage and number of administrations is used as the standard. The results show that the diquafosol sodium eye drops of the present invention can meet the requirements when administered 3 times, which significantly reduces the number of administrations compared to the commercially available product dosage of 5-6 times.

[0019] Beneficial effects of the present invention: The diquafosol sodium and sodium hyaluronate pharmaceutical composition and eye drops thereof disclosed in the present invention: (1) Sodium hyaluronate has the dual effects of a thickener and a moisturizer. Within the preferred dosage range, without adding other thickeners and moisturizers, it continues to maintain the original therapeutic effect of the existing marketed quafosol sodium eye drops, reduces the number of uses, and stabilizes the local drug concentration of quafosol sodium in the eye, with good patient compliance.

[0020] (2) The present invention can effectively prevent and treat dry eye problems while reducing the frequency of use under the premise of reducing the dosage of the drug; sodium hyaluronate is not absorbed after local application to the eye, and there is no evidence that sodium hyaluronate can penetrate the cornea. Even if it is injected into the anterior chamber of the eye, there is only a negligible concentration in the blood vessels and it is quickly metabolized by the liver, so there is no systemic toxic reaction. In this way, the composition reduces the drug concentration and can also reduce the frequency of use of diquafosol sodium, avoiding long-term use and side effects on the human body.

[0021] (3) The preparation process of the present invention is simple, the cost is low, and the economic benefits are significant. At the same time, the present invention prolongs the retention time of the drug in the eye, thereby prolonging the therapeutic effect and shortening the course of the disease, and has excellent application value and practical significance. Implementation

[0022] In order to further explain the technical means and scientific methods adopted by the present invention to achieve the predetermined invention purpose, a composition of diquafosol sodium and its eye drops and corresponding preparation method proposed in the present invention, and its specific implementation examples are described in detail as follows: The material information used in this embodiment is as follows: Table 2 Material information of examples

[0023] Example 1: Diquafosol sodium-sodium hyaluronate ophthalmic composition Diquafosol Sodium 2.5% Sodium hyaluronate 0.05% Add water for injection to 100% Example 2: Diquafosol sodium-sodium hyaluronate ophthalmic composition 1% diquafosol sodium eye drops Diquafosol Sodium 1% Sodium hyaluronate 0.05% Anhydrous disodium hydrogen phosphate 0.1% Sodium chloride 0.45% Potassium chloride 0.15% Sodium hydroxide 0.001% Hydrochloric acid 0.001% The preparation process of this embodiment specifically includes the following steps: (1) Weigh sodium chloride and potassium chloride in order and add them into a preparation cup containing 10% of the total amount of water for injection and stir to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the prescribed amount of sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, control the temperature of the dissolution process at 60±5°C, and cool to room temperature after complete dissolution; (4) Weigh anhydrous disodium hydrogen phosphate and diquafosol sodium, add 30% of the total amount of water for injection and dissolve at room temperature; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution to 7.0±0.2 using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid according to the specific situation; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) Filter the solution obtained in step (7) once through a 0.45 μm microporous filter membrane in a dust hood simulating a Class B production environment; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust hood simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain a finished product.

[0024] Example 3: Diquafosol sodium-sodium hyaluronate ophthalmic composition 3% diquafosol sodium eye drops Diquafosol Sodium 3% Sodium hyaluronate 0.05% Anhydrous disodium hydrogen phosphate 0.2% Benzalkonium chloride 0.01% Sodium chloride 0.45% Potassium chloride 0.15% Sodium hydroxide 0.002% Hydrochloric acid 0.001% The preparation process of this embodiment specifically includes the following steps: (1) Weigh sodium chloride, potassium chloride, and anhydrous disodium hydrogen phosphate in sequence and add them into a preparation cup containing 10% of the total amount of water for injection, stirring to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the prescribed amount of sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, control the temperature of the dissolution process at 60±5°C, and cool to room temperature after complete dissolution; (4) Weigh benzalkonium chloride and diquafosol sodium, add 30% of the total amount of water for injection and dissolve at room temperature; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution to 7.0±0.2 using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid according to the specific situation; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) Filter the solution obtained in step (7) once through a 0.45 μm microporous filter membrane in a dust hood simulating a Class B production environment; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust hood simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain a finished product.

[0025] Example 4: Diquafosol sodium-sodium hyaluronate ophthalmic composition 5% diquafosol sodium eye drops Diquafosol Sodium 5% Sodium hyaluronate 0.05% Anhydrous disodium hydrogen phosphate 0.3% Sodium chloride 0.45% Potassium chloride 0.15% Sodium hydroxide 0.002% Hydrochloric acid 0.001% The preparation process of this embodiment specifically includes the following steps: (1) Weigh sodium chloride, potassium chloride, and anhydrous disodium hydrogen phosphate in sequence and add them into a preparation cup containing 10% of the total amount of water for injection, stirring to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the prescribed amount of sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, control the temperature of the dissolution process at 60±5°C, and cool to room temperature after complete dissolution; (4) Weigh diquafosol sodium and add 30% of the total amount of water for injection to dissolve at room temperature; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid according to the specific situation until the pH value reaches 7.0±0.2; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) Filter the solution obtained in step (7) once through a 0.45 μm microporous filter membrane in a dust hood simulating a Class B production environment; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust hood simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain a finished product.

[0026] Example 5: Diquafosol sodium-sodium hyaluronate ophthalmic composition 2.5% diquafosol sodium eye drops Diquafosol Sodium 2.5% Sodium hyaluronate 0.05% Anhydrous disodium hydrogen phosphate 0.3% Sodium chloride 0.45% Potassium chloride 0.15% Sodium hydroxide 0.002% Hydrochloric acid 0.001% The preparation process of this embodiment specifically includes the following steps: (1) Weigh sodium chloride, potassium chloride, and anhydrous disodium hydrogen phosphate in sequence and add them into a preparation cup containing 10% of the total amount of water for injection, stirring to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the prescribed amount of sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, control the temperature of the dissolution process at 60±5°C, and cool to room temperature after complete dissolution; (4) Weigh diquafosol sodium and add 30% of the total amount of water for injection to dissolve at room temperature; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid according to the specific situation until the pH value reaches 7.0±0.2; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) Filter the solution obtained in step (7) once through a 0.45 μm microporous filter membrane in a dust hood simulating a Class B production environment; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust hood simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain a finished product.

[0027] Example 6 Commercially available sodium hyaluronate eye drops Hyalein ® Example 7 Commercially available diquafosol sodium eye drops Diquas ® Example 8 Comparison of product quality stability results in Examples 2, 3, 4, and 5 Table 3 Stability results of the products in the examples

[0028] The results show that the main quality indicators of samples of Examples 2, 3, 4 and 5 all meet the requirements during the long-term inspection for 12 months and the accelerated inspection for 6 months, indicating that the samples prepared according to the prescription process of the present invention have good stability.

[0029] Example 9 Quality Evaluation of Examples 1-7 The inventors prepared eye drops with a preferred amount of sodium hyaluronate and diquafosol sodium composition (Example 1), anhydrous disodium hydrogen phosphate, potassium chloride, sodium chloride, sodium hydroxide and hydrochloric acid. The detailed prescription is shown in Examples 2-5. The eye drops were compared with the sodium hyaluronate eye drops Hyalein available on the market abroad. ®Diquas ® (Examples 6 and 7) were used to compare and evaluate the quality of the preparations. See Table 4 below for details.

[0030] Table 4 Quality evaluation results of diquafosol sodium eye drops with different prescriptions

Claims

1. A solution-type ophthalmic pharmaceutical composition of diquafosol sodium, characterized in that: The pharmaceutical composition consists of diquafosol sodium and sodium hyaluronate, wherein the amount of diquafosol sodium is 1%-5%, and the amount of sodium hyaluronate is 0.01%-0.1% based on W / V.

2. A solution-type ophthalmic pharmaceutical composition of diquafosol sodium according to claim 1, characterized in that: The dosage of diquafosol sodium is 2.5%, and the dosage of sodium hyaluronate is 0.05%.

3. A solution-type ophthalmic pharmaceutical composition of diquafosol sodium according to claim 1, characterized in that: The pharmaceutical composition comprises anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride, sodium hydroxide, hydrochloric acid and water for injection.

4. A solution-type ophthalmic pharmaceutical composition of diquafosol sodium according to any one of claims 1 to 3, characterized in that: The preparation method comprises: (1) Weigh sodium chloride, potassium chloride, and anhydrous disodium hydrogen phosphate and add them in sequence into a preparation cup containing 10% of the total amount of water for injection, and stir to dissolve; (2) Add 40% of the total amount of water for injection to the predissolving cup; (3) Transfer the solution in (1) to (2), stir and mix evenly, and use 0.1 mol / L sodium hydroxide solution to adjust the pH value of the solution to between 6.5±0.2; adjust the stirring speed, accurately weigh the sodium hyaluronate, slowly add it to the pre-dissolving cup, stir until the sodium hyaluronate is completely dissolved, and cool to room temperature after complete dissolution; (4) Weigh diquafosol sodium and add 30% of the total amount of water for injection to dissolve; (5) Add step (4) into step (3), stir and mix, mix the resulting solutions, add water for injection to make the total volume reach 90% and stir evenly; (6) Determine the pH value of the solution obtained in step (5), and adjust the pH value of the solution using 0.1 mol / L sodium hydroxide solution / dilute hydrochloric acid until the pH value reaches 7.0±0.2; (7) Add water for injection to the full volume (1000 ml) and stir evenly; (8) In a dust hood simulating a Class B production environment, the solution obtained in step (7) was filtered once through a 0.45 μm microporous filter membrane; (9) Filter the solution obtained in step (6) once through two 0.22 μm microporous filter membranes connected in series; (10) In a dust hood simulating a Class B production environment, the qualified solution obtained in step (7) is filled into a single-dose bottle packaging container and sealed to obtain a finished product.

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