Liquid preparation containing tobramycin and dexamethasone as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a liquid preparation containing tobramycin and dexamethasone as well as a preparation method and application of the liquid preparation. The liquid preparation containing tobramycin and dexamethasone takes water as a solvent, and contains tobramycin, dexamethasone, hydroxyethyl cellulose, edetate disodium, sodium sulfate, teloxpol, sodium chloride and benzalkonium chloride. Wherein the weight-average molecular weight of the hydroxyethyl cellulose is 0.3 * 10 < 6 > Dalton to 1.3 * 10 < 6 > Dalton. According to the liquid preparation containing tobramycin and dexamethasone provided by the invention, the long-term storage safety and stability of the liquid preparation in terms of sensitization can be remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a liquid preparation containing tobramycin and dexamethasone, and a preparation method and use thereof. Background Art

[0002] Tobramycin and dexamethasone eye drops belong to a compound preparation, and their main effects are anti-infection, anti-inflammatory, and reducing edema, etc. (1) Anti-infection: Tobramycin and dexamethasone eye drops are mainly composed of tobramycin and dexamethasone, both of which belong to antibiotics and can achieve an anti-infection effect. (2) Anti-inflammatory: The drug also has an anti-inflammatory effect and can be used to treat inflammatory diseases of the eye, such as keratitis, conjunctivitis, etc., and can effectively inhibit the inflammatory reaction and relieve uncomfortable symptoms. (3) Reducing edema: This drug can also be used to improve the edema caused by diseases such as blepharitis, meibomian gland inflammation, and dacryocystitis, which is helpful for improving uncomfortable symptoms of the eye.

[0003] Tobramycin and dexamethasone eye drops is a compound preparation containing an aminoglycoside antibiotic and a corticosteroid (trade name Tobradex) launched by Alcon Laboratories in the late 1980s, and is currently used to treat steroid-responsive inflammatory eye diseases that are suitable for corticosteroid treatment and have bacterial eye infections or risk of infection. The most common adverse reactions of Tobradex are hypersensitivity reactions and local toxicity reactions. At present, there is no relevant report in the prior art on how to solve the hypersensitivity reactions and local toxicity reactions of Tobradex. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a liquid preparation containing tobramycin and dexamethasone, and a preparation method and use thereof. The liquid preparation containing tobramycin and dexamethasone provided by the present invention can significantly improve its long-term storage safety and stability in terms of sensitization.

[0005] The technical solution of the present invention is as follows:

[0006] A liquid preparation containing tobramycin and dexamethasone, wherein the liquid preparation uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; wherein, the weight average molecular weight of the hydroxyethyl cellulose is 0.3×10 6 Dalton to 1.3×10 6 Dalton.

[0007] Preferably, the weight average molecular weight of the hydroxyethyl cellulose is 0.72×10 6 Dalton to 1.3×10 6 Dalton.

[0008] More preferably, the weight-average molecular weight of the hydroxyethyl cellulose is 1.0×10 6 Da.

[0009] Preferably, the liquid preparation contains: tobramycin 2.4 - 3.6 mg / mL, dexamethasone 0.8 - 1.2 mg / mL, hydroxyethyl cellulose 2 - 3 mg / mL, disodium edetate 0.08 - 0.12 mg / mL, sodium sulfate 9.6 - 14.4 mg / mL, tyloxapol 0.4 - 0.6 mg / mL, sodium chloride 2.4 - 3.6 mg / mL, and benzalkonium chloride 0.08 - 0.12 mg / mL.

[0010] More preferably, the liquid preparation contains: tobramycin 3 mg / mL, dexamethasone 1 mg / mL, hydroxyethyl cellulose 2.5 mg / mL, disodium edetate 0.1 mg / mL, sodium sulfate 12 mg / mL, tyloxapol 0.5 mg / mL, sodium chloride 3 mg / mL, and benzalkonium chloride 0.1 mg / mL.

[0011] Another object of the present invention is to provide a method for preparing the above-mentioned liquid preparation containing tobramycin and dexamethasone, which includes the following steps:

[0012] S1 Under stirring conditions, hydroxyethyl cellulose is added to a partial prescription amount of water, and stirring is continued until completely dissolved, then sterilized and filtered to obtain a filtrate, which is solution A;

[0013] S2 Tyloxapol is formulated into a tyloxapol solution, and benzalkonium chloride is formulated into a benzalkonium chloride solution;

[0014] S3 Under stirring conditions, disodium edetate, sodium sulfate, the tyloxapol solution, sodium chloride, the benzalkonium chloride solution, and tobramycin are sequentially added to a partial prescription amount of water, and stirring is continued until completely dissolved, and the pH is adjusted,

[0015] filtered to obtain a filtrate, which is solution B;

[0016] S4 After sterilizing dexamethasone, it is added to solution B and dispersed evenly to obtain solution C;

[0017] S5 Solution C is added to solution A, a partial prescription amount of water is added, aseptically filtered, then water is added to the full volume, homogenized, stirred, and filled.

[0018] Preferably, the temperature of water in steps S1, S3, and S5 is 18 - 30 °C; the stirring in steps S1 and S3 is carried out at a rotation speed of 140 - 360 r / min; the homogenization speed in step S5 is 1500 - 3000 r / min.

[0019] Preferably, the sterilization in step S1 is steam sterilization, which is carried out at 121°C to 126°C for 30 to 35 minutes, and continuous stirring is carried out during the sterilization process; the water in a partial prescription amount in step S1 and step S3 refers to 35 to 40% of the prescription amount of water, and the water in a partial prescription amount in step S5 refers to 10 to 15% of the prescription amount of water.

[0020] Another object of the present invention is to provide the use of the above-mentioned liquid preparation containing tobramycin and dexamethasone or the liquid preparation containing tobramycin and dexamethasone prepared by the preparation method of the above-mentioned liquid preparation containing tobramycin and dexamethasone in the preparation of a drug for treating inflammatory eye diseases.

[0021] The sensitizing substances in drugs include active ingredients, excipients and impurities. For example, the dexamethasone structure contains a primary alcohol hydroxyl group, a tertiary alcohol hydroxyl group and multiple secondary alcohol hydroxyl groups, and the tobramycin structure contains a primary amine amino group, several secondary amine amino groups and secondary alcohol hydroxyl groups. Therefore, dehydration reactions between the same molecules or different molecules may occur during mixing or storage, generating dimers, thereby increasing the sensitization risk of the preparation. Different molecular weights of the same generic name polymer excipients may have very different physicochemical properties, which may affect the quality parameters of the preparation product, including the stability of the active ingredient. Through a large number of creative experiments, the present invention finds that adding hydroxyethyl cellulose with a specific weight average molecular weight to the liquid preparation containing tobramycin and dexamethasone can improve the stability of the tobramycin dexamethasone liquid preparation, especially reduce its sensitization after long-term storage. There is no prior art technical inspiration for improving the stability of the tobramycin dexamethasone liquid preparation by adjusting the weight average molecular weight of hydroxyethyl cellulose, especially reducing its sensitization and other common toxicity risks after long-term storage.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] (1) In vitro tests show that the liquid preparation of the present invention can significantly reduce the risk of formation of high molecular weight impurities.

[0024] (2) The liquid preparation containing tobramycin and dexamethasone provided by the present invention can significantly improve its long-term storage safety and stability in terms of sensitization. Detailed implementation manners

[0025] The present invention will be further described below through the description of specific implementation manners, but this is not a limitation to the present invention. Those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as they do not depart from the basic idea of the present invention, they are all within the scope of the present invention.

[0026] Main materials and sources

[0027] All kinds of raw and auxiliary materials used in the embodiments and comparative examples of the present invention have high commercial accessibility and are purchased from manufacturers publicly disclosed in the registration information database of raw materials, auxiliary materials and packaging materials of the Center for Drug Evaluation (CDE) of the National Medical Products Administration. Among them, the key auxiliary material hydroxyethyl cellulose (HEC) is purchased from Ashland (China) Investment Co., Ltd., and its specification number and key physical and chemical parameters are shown in Table 1.

[0028] Table 1 Specification number and key physical and chemical parameters of hydroxyethyl cellulose in the present invention and comparative examples

[0029]

[0030]

[0031] Note: "Concentration (%)" in Table 1 refers to the concentration when measuring the Brookfield viscosity.

[0032] Example 1, A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0033] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride and benzalkonium chloride; wherein, the hydroxyethyl cellulose is HEC-1, and the weight-average molecular weight of the hydroxyethyl cellulose is 1.3×10 6 Dalton; the liquid preparation contains: tobramycin 2.4 mg / mL, dexamethasone 0.8 mg / mL, hydroxyethyl cellulose 2 mg / mL, disodium edetate 0.08 mg / mL, sodium sulfate 9.6 mg / mL, tyloxapol 0.4 mg / mL, sodium chloride 2.4 mg / mL and benzalkonium chloride 0.08 mg / mL.

[0034] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0035] S1 Take 400 mL of sterilized water (temperature 18 °C), place it in the liquid preparation tank 1, add hydroxyethyl cellulose (addition amount 2 g) to the sterilized water under stirring (rotation speed 140 rpm), continue stirring until completely dissolved, perform steam sterilization at 121 °C for 30 minutes under stirring, and filter with a 20 μm filter element to obtain a filtrate, which is solution A;

[0036] S2 Prepare a tyloxapol solution containing 400 mg of tyloxapol and a benzalkonium chloride solution containing 80 mg of benzalkonium chloride;

[0037] Take 400 mL of sterilized water (at a temperature of 18°C) and place it in the liquid preparation tank 2. Under stirring (at a rotation speed of 140 rpm), successively add disodium edetate (the addition amount is 80 mg), sodium sulfate (the addition amount is 9.6 g), tyloxapol solution (containing 400 mg of tyloxapol), sodium chloride (the addition amount is 2.4 g), benzalkonium chloride solution (containing 80 mg of benzalkonium chloride), and tobramycin (the addition amount is 2.4 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until completely dissolved, adjust the pH to 6 with 1 mol / L sulfuric acid solution, and perform pressure filtration through two - stage 0.22 μm filters to obtain a filtrate, which is solution B;

[0038] Take dexamethasone (the dosage is 800 mg), sterilize it at 160°C for 2 hours in a dry - heat sterilization cabinet, and then add it to solution B and disperse it evenly to obtain solution C;

[0039] Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 18°C), perform pressure filtration through two - stage 0.22 μm filters, then add sterilized water (at 18°C) to make up to 1000 mL, perform high - shear homogenization, set the rotation speed at 1500 rpm, and the shearing time at 30 min. After the homogenization is completed, start stirring, and stir at a speed of 20 rpm until the filling is completed.

[0040] Example 2: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0041] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC - 1, and the weight - average molecular weight of the hydroxyethyl cellulose is 1.3×10 6 Daltons; the liquid preparation contains: 3.6 mg / mL of tobramycin, 1.2 mg / mL of dexamethasone, 3 mg / mL of hydroxyethyl cellulose, 0.12 mg / mL of disodium edetate, 14.4 mg / mL of sodium sulfate, 0.6 mg / mL of tyloxapol, 3.6 mg / mL of sodium chloride, and 0.12 mg / mL of benzalkonium chloride.

[0042] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0043] Take 400 mL of sterilized water (at a temperature of 30°C) and place it in the liquid preparation tank 1. Under stirring (at a rotation speed of 360 rpm), add hydroxyethyl cellulose (the addition amount is 3 g) to the sterilized water, continue stirring until completely dissolved, perform steam sterilization at 126°C for 35 minutes under stirring, and filter through a 20 - μm filter element to obtain a filtrate, which is solution A;

[0044] S2 Prepare tyloxapol into a tyloxapol solution containing 600 mg of tyloxapol, and prepare benzalkonium chloride into a benzalkonium chloride solution containing 120 mg of benzalkonium chloride;

[0045] S3 Take 400 mL of sterilized water (at a temperature of 30 °C) and place it in the liquid preparation tank 2. Under stirring (at a rotation speed of 360 rpm), sequentially add disodium edetate (the addition amount is 120 mg), sodium sulfate (the addition amount is 14.4 g), tyloxapol solution (containing 600 mg of tyloxapol), sodium chloride (the addition amount is 3.6 g), benzalkonium chloride solution (containing 120 mg of benzalkonium chloride), and tobramycin (the addition amount is 3.6 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until completely dissolved, adjust the pH to 6.5 with 1 mol / L sulfuric acid solution, and perform pressure filtration through two - stage 0.22 μm filters to obtain a filtrate, which is solution B;

[0046] S4 Take dexamethasone (the dosage is 1200 mg), sterilize it at 165 °C in a dry - heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0047] S5 Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 30 °C), perform pressure filtration through two - stage 0.22 μm filters, then add sterilized water (at 30 °C) to make up to 1000 mL, and perform high - shear homogenization. Set the rotation speed to 3000 rpm and the shear time to 30 min. After the homogenization is completed, start stirring, and the stirring speed is 40 rpm until the filling is completed.

[0048] Example 3: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0049] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC - 2, and the weight - average molecular weight of the hydroxyethyl cellulose is 1.0×10 6 Daltons; the liquid preparation contains: tobramycin 2.4 mg / mL, dexamethasone 0.8 mg / mL, hydroxyethyl cellulose 2 mg / mL, disodium edetate 0.08 mg / mL, sodium sulfate 9.6 mg / mL, tyloxapol 0.4 mg / mL, sodium chloride 2.4 mg / mL, and benzalkonium chloride 0.08 mg / mL.

[0050] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0051] S1 Take 400 mL of sterilized water (at a temperature of 18 °C) and place it in the liquid preparation tank 1. While stirring (at a rotation speed of 140 rpm), add hydroxyethyl cellulose (the addition amount is 2 g) to the sterilized water, and continue stirring until it is completely dissolved. Then, under stirring, perform steam sterilization at 121 °C for 30 minutes, and filter through a 20-μm filter element to obtain a filtrate, which is solution A;

[0052] S2 Prepare a tyloxapol solution containing 400 mg of tyloxapol, and prepare a benzalkonium chloride solution containing 80 mg of benzalkonium chloride;

[0053] S3 Take 400 mL of sterilized water (at a temperature of 18 °C) and place it in the liquid preparation tank 2. While stirring (at a rotation speed of 140 rpm), sequentially add disodium edetate (the addition amount is 80 mg), sodium sulfate (the addition amount is 9.6 g), the tyloxapol solution (containing 400 mg of tyloxapol), sodium chloride (the addition amount is 2.4 g), the benzalkonium chloride solution (containing 80 mg of benzalkonium chloride), and tobramycin (the addition amount is 2.4 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until it is completely dissolved, and adjust the pH to 6 with 1 mol / L sulfuric acid solution. Perform pressure filtration through two 0.22-μm filters to obtain a filtrate, which is solution B;

[0054] S4 Take dexamethasone (the dosage is 800 mg), sterilize it at 160 °C in a dry heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0055] S5 Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 18 °C), perform pressure filtration through two 0.22-μm filters, then add sterilized water (18 °C) to make up to 1000 mL, and perform high-shear homogenization. Set the rotation speed to 1500 rpm and the shearing time to 30 min. After the homogenization is completed, start stirring, and the stirring speed is 20 rpm until the filling is completed.

[0056] Example 4: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0057] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC-2, and the weight-average molecular weight of the hydroxyethyl cellulose is 1.0×10 6 Daltons; the liquid preparation contains: tobramycin 3.6 mg / mL, dexamethasone 1.2 mg / mL, hydroxyethyl cellulose 3 mg / mL, disodium edetate 0.12 mg / mL, sodium sulfate 14.4 mg / mL, tyloxapol 0.6 mg / mL, sodium chloride 3.6 mg / mL, and benzalkonium chloride 0.12 mg / mL.

[0058] The preparation method of the liquid preparation containing tobramycin and dexamethasone comprises the following steps:

[0059] S1 Take 400 mL of sterilized water (temperature: 30 °C), place it in the liquid preparation tank 1, and under stirring (rotation speed: 360 rpm), add hydroxyethyl cellulose (dosage: 3 g) to the sterilized water. Continue stirring until it is completely dissolved. Then, under stirring, perform steam sterilization at 126 °C for 35 minutes, and filter with a 20-μm filter element to obtain a filtrate, which is solution A.

[0060] S2 Prepare a tyloxapol solution containing 600 mg of tyloxapol, and prepare a benzalkonium chloride solution containing 120 mg of benzalkonium chloride.

[0061] S3 Take 400 mL of sterilized water (temperature: 30 °C), place it in the liquid preparation tank 2, and under stirring (rotation speed: 360 rpm), sequentially add disodium edetate (dosage: 120 mg), sodium sulfate (dosage: 14.4 g), the tyloxapol solution (containing 600 mg of tyloxapol), sodium chloride (dosage: 3.6 g), the benzalkonium chloride solution (containing 120 mg of benzalkonium chloride), and tobramycin (dosage: 3.6 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until it is completely dissolved, and adjust the pH to 6.5 with 1 mol / L sulfuric acid solution. Perform pressure filtration through two-stage 0.22-μm filters to obtain a filtrate, which is solution B.

[0062] S4 Take dexamethasone (dosage: 1200 mg), sterilize it in a dry heat sterilization cabinet at 165 °C for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C.

[0063] S5 Add solution C to solution A, then add 100 mL of sterilized water (temperature: 30 °C). Perform pressure filtration through two-stage 0.22-μm filters, and then add sterilized water (30 °C) to make the volume reach 1000 mL. Perform high-shear homogenization, set the rotation speed at 3000 rpm, and the shearing time at 30 min. After the homogenization is completed, start stirring, and keep the stirring speed at 40 rpm until the filling is completed.

[0064] Example 5. A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0065] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride. Among them, the hydroxyethyl cellulose is HEC-3, and the weight-average molecular weight of the hydroxyethyl cellulose is 0.72×10 6Dalton; the liquid preparation contains: tobramycin 2.4 mg / mL, dexamethasone 0.8 mg / mL, hydroxyethyl cellulose 2 mg / mL, disodium edetate 0.08 mg / mL, sodium sulfate 9.6 mg / mL, tyloxapol 0.4 mg / mL, sodium chloride 2.4 mg / mL, and benzalkonium chloride 0.08 mg / mL.

[0066] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0067] S1 Take 400 mL of sterilized water (temperature 18 °C), place it in the liquid preparation tank 1, and under stirring (rotation speed 140 rpm), add hydroxyethyl cellulose (addition amount 2 g) to the sterilized water, continue stirring until completely dissolved, and sterilize with steam at 121 °C for 30 minutes under stirring, then filter through a 20 μm filter element to obtain a filtrate, which is solution A;

[0068] S2 Prepare a tyloxapol solution containing 400 mg of tyloxapol and a benzalkonium chloride solution containing 80 mg of benzalkonium chloride;

[0069] S3 Take 400 mL of sterilized water (temperature 18 °C), place it in the liquid preparation tank 2, and under stirring (rotation speed 140 rpm), sequentially add disodium edetate (addition amount 80 mg), sodium sulfate (addition amount 9.6 g), the tyloxapol solution (containing 400 mg of tyloxapol), sodium chloride (addition amount 2.4 g), the benzalkonium chloride solution (containing 80 mg of benzalkonium chloride), and tobramycin (addition amount 2.4 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material, stir until completely dissolved, adjust the pH to 6 with 1 mol / L sulfuric acid solution, and perform two-stage filtration through a 0.22 μm filter press to obtain a filtrate, which is solution B;

[0070] S4 Take dexamethasone (usage amount 800 mg), sterilize it at 160 °C in a dry heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0071] S5 Add solution C to solution A, then add 100 mL of sterilized water (temperature 18 °C), perform two-stage filtration through a 0.22 μm filter press, add sterilized water (18 °C) to make up to 1000 mL, and perform high-shear homogenization, set the rotation speed at 1500 rpm, the shearing time at 30 min. After homogenization, start stirring, and the stirring speed is 20 rpm until the filling is completed.

[0072] Example 6. A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0073] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; wherein, the hydroxyethyl cellulose is HEC-3, and the weight-average molecular weight of the hydroxyethyl cellulose is 0.72×10 6 Daltons; the liquid preparation contains: 3.6 mg / mL of tobramycin, 1.2 mg / mL of dexamethasone, 3 mg / mL of hydroxyethyl cellulose, 0.12 mg / mL of disodium edetate, 14.4 mg / mL of sodium sulfate, 0.6 mg / mL of tyloxapol, 3.6 mg / mL of sodium chloride, and 0.12 mg / mL of benzalkonium chloride.

[0074] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0075] S1 Take 400 mL of sterilized water (temperature 30°C), place it in the liquid preparation tank 1, and add hydroxyethyl cellulose (the addition amount is 3 g) to the sterilized water under stirring (rotation speed 360 rpm), continue stirring until completely dissolved, sterilize with steam at 126°C for 35 minutes under stirring, and filter through a 20-μm filter element to obtain a filtrate, which is solution A;

[0076] S2 Prepare a tyloxapol solution containing 600 mg of tyloxapol, and prepare a benzalkonium chloride solution containing 120 mg of benzalkonium chloride;

[0077] S3 Take 400 mL of sterilized water (temperature 30°C), place it in the liquid preparation tank 2, and sequentially add disodium edetate (the addition amount is 120 mg), sodium sulfate (the addition amount is 14.4 g), the tyloxapol solution (containing 600 mg of tyloxapol), sodium chloride (the addition amount is 3.6 g), the benzalkonium chloride solution (containing 120 mg of benzalkonium chloride), and tobramycin (the addition amount is 3.6 g) to the sterilized water under stirring (rotation speed 360 rpm). After adding each material, wait until it is completely dissolved before adding the next material, stir until completely dissolved, adjust the pH to 6.5 with 1 mol / L sulfuric acid solution, and perform pressure filtration through two 0.22-μm filters to obtain a filtrate, which is solution B;

[0078] S4 Take dexamethasone (the dosage is 1200 mg), sterilize it at 165°C in a dry heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0079] S5 Add solution C to solution A, then add 100 mL of sterilized water (temperature 30°C), perform pressure filtration through two 0.22-μm filters, add sterilized water (30°C) to make up to 1000 mL, perform high-shear homogenization, set the rotation speed to 3000 rpm, the shearing time to 30 min, start stirring after homogenization is completed, and the stirring speed is 40 rpm until filling is completed.

[0080] Example 7. A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0081] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride and benzalkonium chloride; wherein, the hydroxyethyl cellulose is HEC-4, and the weight-average molecular weight of the hydroxyethyl cellulose is 0.30×10 6 Dalton; the liquid preparation contains: 2.4 mg / mL of tobramycin, 0.8 mg / mL of dexamethasone, 2 mg / mL of hydroxyethyl cellulose, 0.08 mg / mL of disodium edetate, 9.6 mg / mL of sodium sulfate, 0.4 mg / mL of tyloxapol, 2.4 mg / mL of sodium chloride and 0.08 mg / mL of benzalkonium chloride.

[0082] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0083] S1 Take 400 mL of sterilized water (temperature 18°C), place it in the dispensing tank 1, and add hydroxyethyl cellulose (dosage 2 g) to the sterilized water under stirring (rotation speed 140 rpm), continue stirring until completely dissolved, sterilize with steam at 121°C for 30 minutes under stirring, and filter through a 20-μm filter element to obtain a filtrate, which is solution A;

[0084] S2 Prepare a tyloxapol solution containing 400 mg of tyloxapol, and prepare a benzalkonium chloride solution containing 80 mg of benzalkonium chloride;

[0085] S3 Take 400 mL of sterilized water (temperature 18°C), place it in the dispensing tank 2, and sequentially add disodium edetate (dosage 80 mg), sodium sulfate (dosage 9.6 g), tyloxapol solution (containing 400 mg of tyloxapol), sodium chloride (dosage 2.4 g), benzalkonium chloride solution (containing 80 mg of benzalkonium chloride) and tobramycin (dosage 2.4 g) to the sterilized water under stirring (rotation speed 140 rpm). After adding each material, wait until it is completely dissolved before adding the next material, stir until completely dissolved, adjust the pH to 6 with 1 mol / L sulfuric acid solution, and perform two-stage 0.22-μm pressure filtration to obtain a filtrate, which is solution B;

[0086] S4 Take dexamethasone (dosage 800 mg), sterilize it at 160°C in a dry heat sterilizer for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0087] Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 18 °C). After filtration through two - stage 0.22 - μm filters, add sterilized water (18 °C) to make up to 1000 mL. Homogenize at high shear with a rotation speed of 1500 rpm and a shearing time of 30 min. After homogenization, start stirring at a speed of 20 rpm until filling is completed.

[0088] Example 8: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0089] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC - 4, and the weight - average molecular weight of the hydroxyethyl cellulose is 0.30×10 6 Daltons; the liquid preparation contains: tobramycin 3.6 mg / mL, dexamethasone 1.2 mg / mL, hydroxyethyl cellulose 3 mg / mL, disodium edetate 0.12 mg / mL, sodium sulfate 14.4 mg / mL, tyloxapol 0.6 mg / mL, sodium chloride 3.6 mg / mL, and benzalkonium chloride 0.12 mg / mL.

[0090] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0091] S1: Take 400 mL of sterilized water (at a temperature of 30 °C) and place it in a liquid - preparation tank 1. Under stirring (rotation speed 360 rpm), add hydroxyethyl cellulose (the addition amount is 3 g) to the sterilized water, continue stirring until completely dissolved, sterilize with steam at 126 °C for 35 minutes, and filter through a 20 - μm filter element to obtain a filtrate, which is solution A.

[0092] S2: Prepare a tyloxapol solution containing 600 mg of tyloxapol and a benzalkonium chloride solution containing 120 mg of benzalkonium chloride.

[0093] S3: Take 400 mL of sterilized water (at a temperature of 30 °C) and place it in a liquid - preparation tank 2. Under stirring (rotation speed 360 rpm), sequentially add disodium edetate (the addition amount is 120 mg), sodium sulfate (the addition amount is 14.4 g), the tyloxapol solution (containing 600 mg of tyloxapol), sodium chloride (the addition amount is 3.6 g), the benzalkonium chloride solution (containing 120 mg of benzalkonium chloride), and tobramycin (the addition amount is 3.6 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until completely dissolved, adjust the pH to 6.5 with 1 mol / L sulfuric acid solution, and filter through two - stage 0.22 - μm filters to obtain a filtrate, which is solution B.

[0094] Take dexamethasone (dosage: 1200 mg), sterilize it at 165 °C in a dry heat sterilizer for 2 hours, and then add it to Solution B, disperse evenly to obtain Solution C;

[0095] Add Solution C to Solution A, then add 100 mL of sterilized water (temperature: 30 °C), perform pressure filtration through two - stage 0.22 μm filters, then add sterilized water (30 °C) to make up to 1000 mL, and perform homogenization by high - shear. Set the rotation speed at 3000 rpm and the shearing time at 30 min. After homogenization, start stirring, with the stirring speed at 40 rpm until the filling is completed.

[0096] Comparative Example 1: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0097] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC - 5, and the weight - average molecular weight of the hydroxyethyl cellulose is 0.09×10 6 Dalton; the liquid preparation contains: tobramycin 2.4 mg / mL, dexamethasone 0.8 mg / mL, hydroxyethyl cellulose 2 mg / mL, disodium edetate 0.08 mg / mL, sodium sulfate 9.6 mg / mL, tyloxapol 0.4 mg / mL, sodium chloride 2.4 mg / mL, and benzalkonium chloride 0.08 mg / mL.

[0098] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0099] Take 400 mL of sterilized water (temperature: 18 °C) and place it in a liquid - preparation tank 1. Under stirring (rotation speed: 140 rpm), add hydroxyethyl cellulose (dosage: 2 g) to the sterilized water, continue stirring until completely dissolved, perform steam sterilization at 121 °C for 30 minutes under stirring, and filter through a 20 μm filter element to obtain a filtrate, which is Solution A;

[0100] Prepare a tyloxapol solution containing 400 mg of tyloxapol and a benzalkonium chloride solution containing 80 mg of benzalkonium chloride;

[0101] Take 400 mL of sterilized water (at a temperature of 18 °C) and place it in the liquid preparation tank 2. Under stirring (at a rotation speed of 140 rpm), sequentially add disodium edetate (addition amount: 80 mg), sodium sulfate (addition amount: 9.6 g), tyloxapol solution (containing 400 mg of tyloxapol), sodium chloride (addition amount: 2.4 g), benzalkonium chloride solution (containing 80 mg of benzalkonium chloride), and tobramycin (addition amount: 2.4 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until completely dissolved, adjust the pH to 6 with 1 mol / L sulfuric acid solution, and perform pressure filtration through two - stage 0.22 μm filters to obtain the filtrate, which is solution B;

[0102] Take dexamethasone (dosage: 800 mg), sterilize it at 160 °C in a dry - heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0103] Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 18 °C), perform pressure filtration through two - stage 0.22 μm filters, then add sterilized water (at 18 °C) to make up to 1000 mL, and perform high - shear homogenization. Set the rotation speed at 1500 rpm and the shearing time at 30 min. After homogenization, start stirring, and keep the stirring speed at 20 rpm until the filling is completed.

[0104] Comparative Example 2: A liquid preparation containing tobramycin and dexamethasone and its preparation method

[0105] The liquid preparation containing tobramycin and dexamethasone uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; among them, the hydroxyethyl cellulose is HEC - 5, and the weight - average molecular weight of the hydroxyethyl cellulose is 0.09×10 6 Dalton; the liquid preparation contains: 3.6 mg / mL of tobramycin, 1.2 mg / mL of dexamethasone, 3 mg / mL of hydroxyethyl cellulose, 0.12 mg / mL of disodium edetate, 14.4 mg / mL of sodium sulfate, 0.6 mg / mL of tyloxapol, 3.6 mg / mL of sodium chloride, and 0.12 mg / mL of benzalkonium chloride.

[0106] The preparation method of the liquid preparation containing tobramycin and dexamethasone includes the following steps:

[0107] Take 400 mL of sterilized water (at a temperature of 30 °C) and place it in the liquid preparation tank 1. Under stirring (at a rotation speed of 360 rpm), add hydroxyethyl cellulose (addition amount: 3 g) to the sterilized water, continue stirring until completely dissolved, perform steam sterilization at 126 °C for 35 minutes under stirring, and filter through a 20 - μm filter element to obtain the filtrate, which is solution A;

[0108] S2 Prepare tyloxapol into a tyloxapol solution containing 600 mg of tyloxapol, and prepare benzalkonium chloride into a benzalkonium chloride solution containing 120 mg of benzalkonium chloride;

[0109] S3 Take 400 mL of sterilized water (at a temperature of 30 °C) and place it in the liquid preparation tank 2. Under stirring (at a rotation speed of 360 rpm), sequentially add disodium edetate (the addition amount is 120 mg), sodium sulfate (the addition amount is 14.4 g), tyloxapol solution (containing 600 mg of tyloxapol), sodium chloride (the addition amount is 3.6 g), benzalkonium chloride solution (containing 120 mg of benzalkonium chloride), and tobramycin (the addition amount is 3.6 g) to the sterilized water. After adding each material, wait until it is completely dissolved before adding the next material. Stir until completely dissolved, adjust the pH to 6.5 with 1 mol / L sulfuric acid solution, and perform pressure filtration through two - stage 0.22 μm filters to obtain a filtrate, which is solution B;

[0110] S4 Take dexamethasone (the dosage is 1200 mg), sterilize it at 165 °C in a dry - heat sterilization cabinet for 2 hours, and then add it to solution B and disperse it evenly to obtain solution C;

[0111] S5 Add solution C to solution A, then add 100 mL of sterilized water (at a temperature of 30 °C), perform pressure filtration through two - stage 0.22 μm filters, then add sterilized water (at 30 °C) to make up to 1000 mL, perform high - shear homogenization, set the rotation speed at 3000 rpm, and the shearing time at 30 min. After the homogenization is completed, start stirring, and the stirring speed is 40 rpm until the filling is completed.

[0112] Test Example 1. Study on the sensitization of degradation products of each formulation

[0113] Take the products obtained by accelerating the degradation of each formulation prepared in Examples 1 - 8 and Comparative Examples 1 - 2 and store them at room temperature (25 ± 2 °C) for 10 months. Use the method disclosed by Yang Huiping et al. in "Study on the Effect of Polysorbate 80 on the Degranulation of Multisource Mast Cells" (Source: Drug Evaluation Research, 2019, 42(03):472 - 478) to measure the effect of each product on promoting the release of histamine from RBL - 2H3 cells (replace the polysorbate solution in this literature with the accelerated degradation products of each formulation of the present invention); at the same time, take the reference preparation of tobramycin dexamethasone eye drops on the US market (trade name "Tobradex", the production date is about 80 days away from the test date), accelerate the degradation under the same conditions as the active control. The results are shown in Table 2.

[0114] Table 2 Comparison of the sensitization results of degradation products of each formulation

[0115] Original Prescription Histamine Release Rate, % Example 1 18.11 Example 2 16.67 Example 3 8.30 Example 4 9.41 Example 5 15.43 Example 6 15.06 Example 7 48.34 Example 8 46.52 Comparative Example 1 61.22 Comparative Example 2 74.28 Tobradex 75.62

[0116] As can be seen from Table 2, the histamine release rates of the products obtained by accelerating the degradation of each formulation prepared in Examples 1-8 of the present invention at room temperature (25±2°C) for 10 months are significantly lower than those of Comparative Examples 1-2 and the active control Tobradex. Thus, it can be seen that the formulation of the present invention can significantly improve its long-term storage safety and stability in terms of sensitization.

[0117] Test Example 2. Study on the antibacterial efficacy of the degradation products of each formulation

[0118] Take the products obtained by accelerating the degradation of each formulation prepared in Examples 1-8 and Comparative Examples 1-2 at room temperature (25±2°C) for 10 months, and determine their antibacterial efficacy against Streptococcus pneumoniae and Moraxella lacunata by the method disclosed in General Chapter <51> of the 2024 edition of the United States Pharmacopeia; at the same time, take the reference preparation of tobramycin dexamethasone eye drops on the US market (trade name "Tobradex", production date about 80 days from the test date) and accelerate the degradation under the same conditions as the active control. The results are shown in Table 3.

[0119] Table 3 Comparison of the antibacterial efficacy results of the degradation products of each formulation

[0120]

[0121] As can be seen from Table 3, the antibacterial efficacy of the products obtained by accelerating the degradation of each formulation prepared in Examples 1-8 of the present invention at room temperature (25±2°C) for 10 months against Streptococcus pneumoniae and Moraxella lacunata is significantly higher than that of Comparative Examples 1-2 and the active control Tobradex.

Claims

1. A liquid preparation containing tobramycin and dexamethasone, characterized in that, The liquid preparation uses water as a solvent and contains tobramycin, dexamethasone, hydroxyethyl cellulose, disodium edetate, sodium sulfate, tyloxapol, sodium chloride, and benzalkonium chloride; wherein, the weight-average molecular weight of the hydroxyethyl cellulose is 0.3×10 6 Daltons to 1.3×10 6 Daltons.

2. The liquid preparation containing tobramycin and dexamethasone according to claim 1, wherein, The weight-average molecular weight of the hydroxyethyl cellulose is 0.72×10 6 Dalton to 1.3×10 6 Dalton.

3. The liquid preparation containing tobramycin and dexamethasone according to claim 2, characterized in that, The weight-average molecular weight of the hydroxyethyl cellulose is 1.0×10 6 Daltons.

4. The liquid preparation containing tobramycin and dexamethasone according to claim 1, wherein The liquid preparation described above contains: tobramycin 2.4 - 3.6 mg / mL, dexamethasone 0.8 - 1.2 mg / mL, hydroxyethyl cellulose 2 - 3 mg / mL, disodium edetate 0.08 - 0.12 mg / mL, sodium sulfate 9.6 - 14.4 mg / mL, tyloxapol 0.4 - 0.6 mg / mL, sodium chloride 2.4 - 3.6 mg / mL, and benzalkonium chloride 0.08 - 0.12 mg / mL.

5. The liquid preparation containing tobramycin and dexamethasone according to claim 4, characterized in that, The liquid preparation described above contains: tobramycin 3 mg / mL, dexamethasone 1 mg / mL, hydroxyethyl cellulose 2.5 mg / mL, disodium edetate 0.1 mg / mL, sodium sulfate 12 mg / mL, tyloxapol 0.5 mg / mL, sodium chloride 3 mg / mL, and benzalkonium chloride 0.1 mg / mL.

6. The preparation method of the liquid preparation containing tobramycin and dexamethasone according to any one of claims 1-5, characterized in that, Comprising the following steps: S1 Under stirring conditions, add hydroxyethyl cellulose to a partial prescription amount of water, continue stirring until completely dissolved, sterilize, filter, and obtain a filtrate, which is solution A; S2 Prepare a tyloxapol solution from tyloxapol and a benzalkonium chloride solution from benzalkonium chloride; S3 Under stirring conditions, sequentially add disodium edetate, sodium sulfate, the tyloxapol solution, sodium chloride, the benzalkonium chloride solution, and tobramycin to a partial prescription amount of water, continue stirring until completely dissolved, adjust the pH, filter, and obtain a filtrate, which is solution B; S4 After sterilizing dexamethasone, add it to solution B and disperse evenly to obtain solution C; S5 Add solution C to solution A, add a partial prescription amount of water, perform sterile filtration, then add water to the full volume, homogenize, stir, and fill.

7. The preparation method of the liquid preparation containing tobramycin and dexamethasone according to claim 6, characterized in that, The temperature of the water in steps S1, S3, and S5 is 18 - 30 °C; the stirring in steps S1 and S3 is carried out at a rotational speed of 140 - 360 r / min; the homogenization speed in step S5 is 1500 - 3000 r / min.

8. The preparation method of the liquid preparation containing tobramycin and dexamethasone according to claim 6, characterized in that, The sterilization in step S1 is steam sterilization, which is carried out at 121 °C - 126 °C for 30 - 35 minutes, and continuous stirring is carried out during the sterilization process; the partial prescription amount of water in steps S1 and S3 refers to 35 - 40% of the prescription amount of water, and the partial prescription amount of water in step S5 refers to 10 - 15% of the prescription amount of water.

9. Use of a liquid preparation containing tobramycin and dexamethasone prepared by the preparation method of the liquid preparation containing tobramycin and dexamethasone according to any one of claims 1 - 5 or the liquid preparation containing tobramycin and dexamethasone according to any one of claims 6 - 8 in the preparation of a drug for treating inflammatory eye diseases.

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