Gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as well as preparation method and application of gel eye drops

Abstract

The invention discloses gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as well as a preparation method and application of the gel eye drops, and belongs to the technical field of medicines. Comprising the following raw materials in parts by weight: 0.8-1.2 parts of bromfenac sodium, 0.8-6 parts of moxifloxacin hydrochloride, 15-30 parts of a gel matrix, 3-15 parts of sodium hyaluronate, 8-12 parts of an osmotic pressure regulator, 7.0-9.0 parts of citric acid, 0.02-0.05 part of sodium citrate and 950-1050 parts of purified water. The bromfenac sodium and the moxifloxacin hydrochloride are compounded, and the gel matrix, the sodium hyaluronate, the osmotic pressure regulator, the citric acid, the sodium citrate and the purified water are matched, so that the compound gel eye drops which are free of preservatives, low in irritation, good in stability, capable of improving the bioavailability of drugs and capable of achieving anti-inflammatory and antibacterial synergistic interaction are achieved, and eye inflammation can be effectively treated.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, its preparation method, and its application. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] The ocular mucosa is fragile and directly exposed to the external environment, making it susceptible to microbial invasion and inflammatory diseases caused by physical and chemical irritants. Infectious conjunctivitis and dry eye syndrome complicated by inflammation are common clinical conditions. In severe cases, these conditions can damage the corneal barrier and impair visual function. Therefore, ophthalmic preparations with both anti-inflammatory and antibacterial effects have become a clinical necessity. Currently, commonly used anti-inflammatory eye drops are represented by bromfenac sodium, while antibacterial eye drops are represented by moxifloxacin hydrochloride. Both are widely used in ophthalmology due to their excellent efficacy.

[0004] In existing technologies, both bromfenac sodium eye drops and moxifloxacin hydrochloride eye drops are marketed as multi-dose solutions. To ensure the storage stability of multi-dose products, both formulations contain borax as a preservative. However, prolonged contact of borax with the ocular surface can damage the integrity of the ocular mucosal barrier, leading to accelerated tear evaporation and inducing or aggravating dry eyes and foreign body sensation, making them extremely unsuitable for people with dry eye syndrome or corneal sensitivity. Simultaneously, bromfenac sodium single-agent formulations require the addition of an oxidant to ensure efficacy stability. Oxidants can increase ocular irritation and also contribute to poor drug stability. Furthermore, combining the two eye drops not only increases the frequency of administration and inconvenience for patients but also increases the combined irritation and burden on the ocular surface because the two formulations may contain different pH adjustment systems, osmotic pressure regulators, and preservatives. While solution-type eye drops are convenient and inexpensive, they have significant drawbacks. Firstly, due to the eye's protective mechanisms, the medication remains in the conjunctival sac for a short time, resulting in low local bioavailability and hindering its effectiveness. Secondly, most of the medication travels with the tears to the nasal cavity and is then absorbed through the mucous membranes into the systemic circulation, increasing the risk of side effects. Although hydrogel technology has been shown to prolong the retention time of medication on the ocular surface, hydrogel eye drops are relatively viscous and prone to microbial growth. Therefore, the addition of preservatives can cause eye irritation and dryness.

[0005] There is a lack of preservative-free, low-irritant, and stable compound eye drops containing bromfenac sodium and moxifloxacin hydrochloride that can improve drug bioavailability and achieve synergistic anti-inflammatory and antibacterial effects, which urgently needs to be developed. Summary of the Invention

[0006] In view of this, the present invention provides a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, a method for preparing the same, and its application.

[0007] In a first aspect, the present invention provides a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, comprising the following raw materials in parts by weight: 0.8-1.2 parts of bromfenac sodium, 0.8-6 parts of moxifloxacin hydrochloride, 15-30 parts of gel matrix, 3-15 parts of sodium hyaluronate, 8-12 parts of osmotic pressure regulator, 7.0-9.0 parts of sodium citrate, 0.02-0.05 parts of citric acid, and 950-1050 parts of purified water.

[0008] Preferably, the gel matrix includes one or more of hydroxypropyl methylcellulose, carbomer, xanthan gum, and hydroxyethyl cellulose.

[0009] Preferably, the weight ratio of sodium bromfenac to moxifloxacin hydrochloride is 1:1 to 1:5; The weight ratio of sodium bromfenac to moxifloxacin hydrochloride is 1:1, 1:2, 1:3, 1:4 or 1:5.

[0010] Preferably, the osmotic pressure regulator is selected from one or more of sorbitol, glycerol, propylene glycol, and mannitol.

[0011] Secondly, the present invention provides a method for preparing the above-mentioned gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride, comprising the following steps: (1) Dissolve the gel matrix and sodium hyaluronate in a portion of purified water, allow them to swell fully, and sterilize at high temperature to obtain a gel matrix dispersion; (2) Dissolve sodium bromfenac and moxifloxacin hydrochloride in part of purified water, then add citric acid, sodium citrate and osmotic pressure regulator, stir evenly, filter to remove bacteria, and obtain the second solution; (3) Mix the second solution obtained in step (2) with the gel matrix dispersion obtained in step (1), add purified water to the required amount, stir, and fill into a single-dose packaging container.

[0012] Preferably, in step (1), the high temperature is 120-130℃.

[0013] Preferably, in step (2), a 0.22μm PVDF filter membrane is used for sterilization.

[0014] Preferably, in step (3), the stirring speed is 1000-2000 rpm, the stirring temperature is 30-40℃, and the stirring time is 30-40 min.

[0015] Preferably, in step (3), the filling volume is 0.4ml to 1.5ml.

[0016] Thirdly, the present invention also provides the application of the above-mentioned gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride, or the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride prepared by the above-mentioned preparation method, in the preparation of anti-inflammatory drugs.

[0017] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) The present invention improves the bioavailability of drugs by combining the gel matrix with sodium hyaluronate.

[0018] The composite hydrogel network formed by these two components not only possesses suitable viscoelasticity to resist blinking clearance, but also enhances the bioadhesion of the formulation through the specific binding of sodium hyaluronate to CD44 receptors on the surface of corneal epithelial cells. This allows the medication to form a stable drug-retention film on the ocular surface, achieving slow and sustained drug release. The direct effect is a significantly prolonged effective duration of action after a single dose, improving patient compliance while fundamentally reducing the risk of systemic drug absorption and potential side effects caused by frequent eye drops.

[0019] (2) This invention demonstrates a synergistic effect in the treatment of ocular inflammation through the combined use of bromfenac sodium and moxifloxacin hydrochloride. Compared with single-dose eye drops, it can more effectively relieve ocular inflammatory symptoms and improve treatment efficacy. While inhibiting the inflammatory response, bromfenac sodium may promote the penetration and distribution of the antibacterial drug moxifloxacin hydrochloride by reducing tissue edema and improving local microcirculation; while moxifloxacin hydrochloride effectively controls bacterial infection, thus eliminating inflammatory stimulation at the source, and the two form a synergistic effect. Furthermore, the buffer salt system composed of citrate and sodium citrate provides the drug with the optimal pH environment to achieve low irritation, avoiding pH imbalance that irritates the ocular surface and preventing damage to the drug structure, further ensuring stability during storage.

[0020] (3) The present invention designs the formulation as a single-dose package, avoiding the addition of preservatives, which is more friendly to people with dry eye syndrome and corneal sensitivity, reduces adverse reactions caused by preservatives, and improves medication safety. The two active ingredients are integrated into a single compound preparation, eliminating the need for patients to use two single preparations in separate drops, thus simplifying the administration process.

[0021] (4) The preparation method of the present invention is simple and easy to apply in industrial production. Attached Figure Description

[0022] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0023] Figure 1 The images show photographs of the left eyeballs of New Zealand rabbits in the normal control group. In the images, a represents rabbits given saline solution for 3 days and b represents rabbits given saline solution for 7 days. Figure 2 The images show photographs of the left eyeballs of the New Zealand rabbits in the model group. In the images, a represents rabbits given saline solution for 3 days and b represents rabbits given saline solution for 7 days. Figure 3 The image shows the left eye of a New Zealand rabbit in the positive control group. In the image, a represents the period after 3 days of drug administration, and b represents the period after 7 days of drug administration. Figure 4 The image shows a photograph of the left eye of a New Zealand rabbit from Example 1, where a represents the period after 3 days of drug administration and b represents the period after 7 days of drug administration. Figure 5 The images show photographs of the left eyes of New Zealand rabbits in the three comparative groups, where a represents the period after 3 days of drug administration and b represents the period after 7 days of drug administration. Figure 6 The image shows the left eye of a New Zealand rabbit in Comparative Example 1, where a represents the period after 3 days of drug administration and b represents the period after 7 days of drug administration. Figure 7 The images show photographs of the left eyeballs of New Zealand rabbits in the two comparative groups. In the figure, a represents the period after 3 days of drug administration, and b represents the period after 7 days of drug administration. Detailed Implementation

[0024] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0025] This invention provides a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, comprising the following raw materials in parts by weight: 0.8-1.2 parts bromfenac sodium, 0.8-6 parts moxifloxacin hydrochloride, 15-30 parts gel matrix, 3-15 parts sodium hyaluronate, 8-12 parts osmotic pressure regulator, 7.0-9.0 parts sodium citrate, 0.02-0.05 parts citric acid, and 950-1050 parts purified water.

[0026] The present invention utilizes sodium bromfenac as a nonsteroidal anti-inflammatory drug (NSAID) to target and inhibit the release of inflammatory mediators in the eye, rapidly relieving redness, swelling, and pain caused by inflammation. Moxifloxacin hydrochloride, as a fluoroquinolone antibacterial drug, can broadly kill common ocular pathogens such as Gram-positive and Gram-negative bacteria, inhibiting infection at its source. Combining these two drugs in the presence of sodium hyaluronate and another gel matrix, a formulation is formed that possesses both anti-inflammatory and antibacterial properties. Simultaneously, sodium hyaluronate's high water-binding capacity and high similarity to glycoprotein molecules in the corneal mucosa result in superior ocular surface binding ability. Together with the other gel matrix, it forms the gel matrix of the eye drops, enhancing the residence time of both drugs on the ocular surface, creating a complementary antibacterial and anti-inflammatory mechanism, and improving bioavailability.

[0027] In an optional embodiment of the present invention, the gel matrix is ​​selected from one or more of hydroxypropyl methylcellulose, carbomer, xanthan gum, and hydroxyethyl cellulose. These materials not only possess good gel-forming ability and biocompatibility, but also each have auxiliary functions. Hydroxypropyl methylcellulose and hydroxyethyl cellulose adhere to the ocular surface through polymer adsorption, mimicking the function of conjunctival mucin, thereby improving the state of reduced ocular mucin and increasing the ocular retention time in the state of reduced tear film. This adsorption is independent of the viscosity of the solution, thus ensuring a long-lasting wetting effect even with very low viscosity solutions. It can synergistically repair the ocular surface mucosa with sodium hyaluronate, making it suitable for people with dry eye syndrome complicated by infection; carbomer can rapidly swell to form a uniform gel in the physiological pH environment of the eye, with optimal viscoelastic properties and strong resistance to blink clearance, making it suitable for postoperative inflammatory scenarios where high drug retention time is required; xanthan gum has good thermal stability, can withstand high-temperature sterilization, avoids damage to the gel structure, and is suitable for large-scale industrial production.

[0028] In an optional embodiment of the present invention, the weight ratio of sodium bromfenac to moxifloxacin hydrochloride is 1:1 to 1:5; The weight ratio of bromfenac sodium to moxifloxacin hydrochloride is 1:1, 1:2, 1:3, 1:4, or 1:5. Firstly, within this range, the solubility of the two drugs in the citrate buffer and gel network achieves an optimal balance, ensuring the required antibacterial and anti-inflammatory efficacy ratio for clinical use while preventing either drug from precipitating due to supersaturation. This is crucial for maintaining the physical and chemical stability of the formulation. Secondly, different ratios of bromfenac sodium to moxifloxacin hydrochloride affect the pH of the gel eye drops. At this weight ratio, it avoids both excessively high moxifloxacin hydrochloride content leading to a low pH and causing eye irritation, and excessively low content leading to insufficient antibacterial effect.

[0029] In an optional embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sorbitol, glycerol, propylene glycol, and mannitol. These osmotic pressure regulators can precisely adjust the osmotic pressure of the eye drops to match the osmotic pressure of the ocular surface tissue, reducing irritation to the ocular surface and improving patient comfort. In gel systems, they can strongly bind with water molecules, helping to maintain the water-containing structure of the gel network, preventing water evaporation or gel shrinkage during storage, further improving the physical stability of the formulation and user comfort.

[0030] This invention provides a method for preparing the above-mentioned gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride, comprising the following steps: (1) Dissolve the gel matrix and sodium hyaluronate in a portion of purified water, allow them to swell fully, and sterilize at high temperature to obtain a gel matrix dispersion; (2) Dissolve sodium bromfenac and moxifloxacin hydrochloride in part of purified water, then add citric acid, sodium citrate and osmotic pressure regulator, stir, filter and sterilize to obtain the second solution; (3) Mix the second solution obtained in step (2) with the gel matrix dispersion obtained in step (1), add purified water to the required amount, stir, and fill into a single-dose packaging container.

[0031] Step (1) First, the gel matrix and sodium hyaluronate are treated separately to ensure that they swell fully and avoid the residue of gel particles affecting the uniformity of the formulation. High-temperature sterilization eliminates microorganisms in the matrix in advance to avoid contamination when mixed with drugs later and ensures the sterility of the preservative-free formulation. Step (2) The active pharmaceutical ingredient and excipients are dissolved separately to avoid the decrease in solubility caused by direct contact between the drug and the gel matrix. Filtration and sterilization further enhance the sterility guarantee. Finally, they are mixed, stirred and filled. Single-dose packaging avoids the addition of preservatives.

[0032] In an optional embodiment of the present invention, the high temperature in step (1) is 120-130℃. This temperature range balances sterility assurance with the integrity of the gel structure. 120-130℃ can completely kill bacterial spores and other microorganisms within 10-20 minutes, meeting the strict sterility requirements of preservative-free ophthalmic preparations and avoiding infection caused by ocular administration. At the same time, this temperature range will not damage the three-dimensional structure of the gel matrix (such as the hydroxyl groups of hydroxypropyl methylcellulose and hydroxyethylcellulose, and the carboxyl groups of carbomer), nor will it affect the adhesion and repair function of sodium hyaluronate, effectively preventing a decrease in gel viscosity or loss of viscoelastic properties.

[0033] In an optional embodiment of the present invention, in step (2), a 0.22 μm PVDF filter membrane is used for sterilization. This filter membrane can trap microorganisms in the preparation, ensuring the sterility of the preservative-free preparation and avoiding the risk of eye infection; at the same time, the PVDF filter membrane has good chemical stability, will not interact with the components in the preparation, will not introduce impurities, and ensures the purity and safety of the preparation.

[0034] In an optional embodiment of the present invention, in step (3), the stirring speed is 1000-2000 rpm, the stirring temperature is 30-40℃, and the stirring time is 30-40 min. The speed of 1000-2000 rpm can avoid the three-dimensional network structure of the gel breaking due to excessive stirring, thus losing its core function of resisting blinking clearance, and can also avoid the problem of uneven mixing of drug and gel due to excessively high / low local concentrations due to excessively slow stirring. The temperature of 30-40℃ can promote the penetration of drug molecules into the gel network structure, improve the drug encapsulation rate, and at the same time, this temperature will not cause the degradation of bromfenac sodium and moxifloxacin hydrochloride, thus ensuring the efficacy. The time of 30-40 min can ensure that the two solutions are fully mixed, avoid the occurrence of stratification, precipitation or abnormal local viscosity after filling, and ultimately ensure the uniformity, stability and accuracy of the dosage of the preparation.

[0035] In an optional embodiment of the present invention, in step (3), the filling volume is 0.4ml to 1.5ml.

[0036] This invention also provides the application of the above-mentioned gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride, or the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride prepared by the above-mentioned method, in the preparation of anti-inflammatory drugs. In this invention, the inflammation treated by the anti-inflammatory drug preferably includes external ocular inflammatory diseases, anterior ocular inflammatory diseases, or prostaglandin-related inflammations, more preferably including blepharitis, conjunctivitis, keratitis, scleritis, postoperative ocular inflammation, and cyclooxygenase-mediated prostaglandin-related inflammations.

[0037] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0038] Example 1 This embodiment provides a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, the formulation of which is shown in Table 1.

[0039] The preparation method of the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride is as follows: (1) Disperse and dissolve hydroxypropyl methylcellulose and sodium hyaluronate in 400ml of purified water, allow to swell for 540min, sterilize at 130℃ for 15min to obtain gel matrix dispersion; (2) Dissolve sodium bromfenac and moxifloxacin hydrochloride in 500ml of purified water, then add citric acid, sodium citrate and osmotic pressure regulator, stir well, and filter with a 0.22μm PVDF filter membrane to obtain the second solution; (3) Mix the second solution obtained in step (2) with the gel matrix dispersion obtained in step (1), add purified water to the required amount, stir at 1500 rpm, stir at 30°C for 30 min, and fill into 1 ml vials.

[0040] Examples 2-4 Gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride were prepared according to the preparation method of Example 1. The compositions of gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride in Examples 2-4 are shown in Table 1.

[0041] Example 5 Based on Example 1, hydroxypropyl methylcellulose was replaced with carbomer, while other components and preparation process remained unchanged.

[0042] Example 6 Based on Example 1, hydroxypropyl methylcellulose was replaced with xanthan gum, while other components and preparation process remained unchanged.

[0043] Example 7 Based on Example 1, hydroxypropyl methylcellulose was replaced with hydroxyethyl cellulose, while other components and preparation process remained unchanged.

[0044] Example 8 Based on Example 1, sorbitol was replaced with glycerol, while other components and preparation process remained unchanged.

[0045] Example 9 Based on Example 1, sorbitol was replaced with propylene glycol, while other components and preparation process remained unchanged.

[0046] Example 10 Based on Example 1, sorbitol was replaced with mannitol, while other components and preparation process remained unchanged.

[0047] Comparative Example 1 A gel eye drop containing bromfenac sodium was prepared according to the preparation method of Example 1. The composition of the gel eye drop containing bromfenac sodium in Comparative Example 1 is shown in Table 1.

[0048] Comparative Example 2 Gel eye drops containing moxifloxacin hydrochloride were prepared according to the preparation method of Example 1. The composition of the gel eye drops containing moxifloxacin hydrochloride in Comparative Example 2 is shown in Table 1.

[0049] Comparative Example 3 Gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride were prepared according to the preparation method of Example 1. The composition of the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride in Comparative Example 3 is shown in Table 1.

[0050] Comparative Example 4 Eye drops containing bromfenac sodium and moxifloxacin hydrochloride were prepared according to the preparation method of Example 1. The composition of eye drops containing bromfenac sodium and moxifloxacin hydrochloride in Comparative Example 4 is shown in Table 1.

[0051] Comparative Example 5 Gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride were prepared according to the preparation method of Example 1. The composition of the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride in Comparative Example 5 is shown in Table 1.

[0052] Table 1. Composition of gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride in Examples 1-4 and Comparative Examples 1-5

[0053] Experimental Example 1 The eye drops of Examples 1-10 and Comparative Examples 1-5 were tested according to the draft quality standard (the quality standard test items were performed in accordance with the 2025 edition of the Chinese Pharmacopoeia). The results are shown in Table 2.

[0054] Table 2: Performance data of gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride from Examples 1-10 and Comparative Examples 1-5

[0055] As can be seen from Table 1, through Examples 1-10, the gel eye drops prepared by the present invention can produce products with both properties and pH that meet the requirements.

[0056] As can be seen from Example 1 and Comparative Example 5, eye drops without added buffer salts have a lower pH, which may cause greater irritation to the eyes. Therefore, it is necessary to add buffer salts to the eye drops.

[0057] Experimental Example 2 Stability test The eye drops of Examples 1-10 and Comparative Example 3 were subjected to accelerated stability testing in a 40℃±2℃ chamber for 30 days. Samples were taken periodically during this period, and the tests were performed according to the Chinese Pharmacopoeia 2025. The results are shown in Table 3.

[0058] Table 3. Stability data of gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride from Examples 1-10 and Comparative Example 3.

[0059] As can be seen from Table 3, the stability of the comparative example 3 gel eye drops without sodium hyaluronate is poor. Therefore, sodium hyaluronate needs to be added to the gel eye drops.

[0060] Experimental Example 3 The duration of ocular retention is an important indicator for evaluating topical ocular formulations. In this experiment, the fluorescein method was used to conduct ocular retention experiments on Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4 of the present invention, and the experimental results were compared.

[0061] 40 μl of green fluorescent protein was added to each of the eye drops in Examples 1, 1, 2, 3, and 4 of this invention. Rabbits were then divided into 5 groups of 6 rabbits each. The heads of 6 healthy rabbits were fixed, and the lower eyelids were lifted to form a small cup shape. Two drops of each of the eye drops from Examples 1, 1, 2, 3, and 4 were instilled into the conjunctival sac of the left eye of each rabbit. After administration, each rabbit's eye was passively closed for 10 seconds. The rabbits were then observed under blue light at a wavelength of 470 nm (green fluorescent protein fluoresces green under blue light at 450–490 nm). The fluorescence fading time of the green fluorescent protein in the conjunctiva and cornea after administration was recorded. The longest fading time of fluorescence in the two sites was defined as the ocular residence time.

[0062] The table below shows the results of ocular retention time measurements for eye drops from Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4.

[0063] Table 4 Results of eye retention time measurement

[0064] As can be seen from Table 4, the comparison of the retention time in the eye between Comparative Example 3 and Example 1, Comparative Example 1 and Comparative Example 2 shows that the addition of sodium hyaluronate to the gel matrix significantly increased the retention time of the eye drops in the eye; while compared with the eye drops without added gel matrix (Comparative Example 4), the eye drops with added gel matrix had an increased retention time in the eye, especially the gel eye drops with added sodium hyaluronate gel matrix had a significantly increased retention time in the eye.

[0065] Experimental Example 4: Drug Efficacy Test 1. Route of administration The test sample is intended for clinical use via eye drops, therefore the eye drop method was adopted for administration.

[0066] 2. Dosage design and basis Positive control and examples: Clinically prescribed dosage: The clinically prescribed dosage for each person is 1-2 drops twice daily. This trial was conducted using the clinical dosage method, with all 7 prescriptions set to be administered twice daily, 2 drops each time.

[0067] 3. Animal identification after grouping Each animal was identified using animal tagging and cage tagging methods.

[0068] 3.1 Animal marking Each group of animals was numbered 1-6. Picric acid was applied to different parts of the animals' fur to mark them. The marking locations are shown in Table 5.

[0069] Table 5 Marked Locations Animal ID in the group stained area Animal ID in the group stained area 01 Top of head 04 dorsal tail root 02 neck 05 Left forelimb 03 Back center 06 Left side of the abdomen 3.2 Cage Marking After grouping the animals, different groups are labeled with cage tags of different colors. The tags include: project number, cage number, sex, group, animal number, project leader, contact number, and experiment start and end dates. The completed cage tags are hung on the front of the enclosure.

[0070] 4. Animal Model Preparation Under local anesthesia with tetracaine gel eye drops, the eyelids are fully opened using an eyelid speculum. A No. 7 corneal trephine is used to gently press the conjunctiva in a clockwise direction, causing a circular injury to the conjunctiva, ideally reaching the Bowman's layer. Two 10 μL tubes are then pipetted into the eye. 9 / ml of Pseudomonas aeruginosa bacterial solution was dropped onto the conjunctiva of the eye, 0.1 ml per eye, infecting the left eye, while the right eye was left untreated, thus creating an animal model of conjunctivitis.

[0071] 5. Animal grouping Group design: A total of 7 groups were set up, namely blank control group, model group, positive control group, example 1, comparative example 1, comparative example 2 and comparative example 3 prescription groups.

[0072] Number of animals: 6 animals per group, totaling 42 animals; Sex ratio: hermaphroditic; Grouping method: On the 3rd day after modeling, animals with successful membrane formation were selected and grouped evenly according to rabbit eye scores.

[0073] See Table 6 below for specific group information.

[0074] Table 6. Dosing regimen and grouping information

[0075] The positive control group consisted of a compound eye drop made up of commercially available bromfenac sodium eye drops and commercially available moxifloxacin hydrochloride eye drops, with a ratio of 1:1.

[0076] 6. Administration Administer the drug daily for 7 consecutive days. After grouping, administer the drug to the left eye of each animal in the treatment group, with the corresponding positive control or test drug given twice daily, 2 drops each time. The model group and the blank group were given an equal volume of physiological saline.

[0077] 7. Indicator Testing 7.1 Weight Measurement Adaptation period: 2 times (the day after purchase and the day of grouping). Dosage period: Test once every 3 days Animals tested: surviving animals in each group During the experiment, the body weight of the model group animals was basically the same as that of the normal group animals (p>0.05); the four test sample groups (positive control group, Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3) were basically the same as those of the model group (p>0.05). This indicates that conjunctivitis modeling has no effect on animal body weight, and the test samples also have no effect on the body weight of the model group animals.

[0078] The results are shown in Table 7.

[0079] Table 7. Body weight of rabbits with bacterial conjunctivitis (±S, n=6)

[0080] 7.2 Symptom Observation Measurement time: 72 hours after modeling, and 3 and 7 days after drug administration.

[0081] Animals tested: Surviving animals in each group.

[0082] Grading Criteria: Ulcers: Ulcers covering more than 70% of the eyeball: 5 points; 50% to less than 70%: 4 points; 30% to less than 50%: 3 points; 20% to less than 30%: 2 points; 1% to less than 20%: 1 point; No ulcers: 0 points. Discharge: Abnormally large discharge: 3 points; Large discharge: 2 points; Small discharge: 1 point; Minimal or no discharge: 0 points. Eyelid Redness and Swelling: Eyelids that are both red and swollen: 2 points; Eyelids that are only red and not swollen: 1 point; Eyelids that are neither red nor swollen: 0 points.

[0083] Eye symptom observation and scoring: In the normal control group, the New Zealand rabbits had normal eyeballs with no discharge, ulcers, or redness, and their scores were 0 during the experiment. 72 hours after membrane creation, the New Zealand rabbits exhibited abundant discharge, numerous ulcers, and significant redness and swelling. In the model group, eye symptoms slightly subsided spontaneously during the observation period, and the scores decreased slightly. In the positive control group and the four prescription groups, symptoms improved to varying degrees with prolonged administration. Example 1 showed the most significant improvement; from day 3 of administration, Example 1 showed a significant difference in scores compared to the model group (p < 0.01), and from day 7 of administration, a significant difference compared to the model control group (p < 0.05), and a significant decrease in scores compared to the positive control group. Comparative Example 3 showed a significant difference in scores compared to the model group from day 5 of administration (p < 0.05). The positive control group showed the second-best results. Starting from day 5 of administration, there was a significant difference in scores compared with the model group (p < 0.01), but the scores were lower than those of control group 3. Control group 1 and control group 2 also showed a certain degree of reduction in eye scores, with significant differences compared with the model group (p < 0.01), but no significant difference compared with the positive control group (p > 0.05).

[0084] The results are shown in Table 8.

[0085] Table 8. Observational scores of rabbit eyes in cases of bacterial conjunctivitis (±S, n=6)

[0086] Note: p < 0.01, p < 0.05, compared with the model group; p > 0.05, compared with the positive control group. 7.3 Representative Photos Twelve hours after the last administration, the left eye of the animal was photographed, and representative photos were selected.

[0087] like Figure 1 a and Figure 1 As shown in b, the New Zealand rabbits in the normal control group showed no discharge, redness, swelling, or ulceration in their eyeballs.

[0088] like Figure 2 a and Figure 2 As shown in b, the New Zealand rabbits in the model group had a large amount of discharge from their eyes on days 3 and 7, with more ulcers and obvious redness and swelling.

[0089] like Figure 3 a and Figure 3 As shown in b, the New Zealand rabbits in the positive control group had more eye discharge, redness, swelling and ulceration on day 3. After 7 days of drug administration, the discharge was significantly reduced, but discharge was still visible, and the redness and swelling were also significantly reduced.

[0090] like Figure 4 a and Figure 4As shown in b, in the New Zealand rabbits of Example 1, eye discharge decreased after 3 days, but redness and ulcers were still visible. After 7 days of administration, discharge was almost non-existent, and redness and ulcers were not observed.

[0091] like Figure 5 a and Figure 5 As shown in b, no eye discharge was observed in the New Zealand rabbits of Comparative Group 3 after 3 days, and no redness or ulcers were observed. After 7 days of drug administration, no discharge was observed, and no redness or ulcers were observed.

[0092] like Figure 6 a and Figure 6 As shown in b, in the control group of New Zealand rabbits, eye discharge decreased after 3 days, but redness and ulcers were still quite obvious. After 7 days of administration, no discharge was observed, but redness and swelling were still visible.

[0093] like Figure 7 a and Figure 7 As shown in b, in the control group 2, the New Zealand rabbits had reduced eye discharge after 3 days, but redness and ulcers were still quite obvious. After 7 days of administration, no discharge was observed, but redness and swelling were still visible.

[0094] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride, characterized in that, The raw materials include the following parts by weight: 0.8-1.2 parts of bromfenac sodium, 0.8-6 parts of moxifloxacin hydrochloride, 15-30 parts of gel matrix, 3-15 parts of sodium hyaluronate, 8-12 parts of osmotic pressure regulator, 7.0-9.0 parts of citric acid, 0.02-0.05 parts of sodium citrate, and 950-1050 parts of purified water.

2. The gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as described in claim 1, characterized in that, The gel matrix is ​​selected from one or more of hydroxypropyl methylcellulose, carbomer, xanthan gum, and hydroxyethyl cellulose.

3. The gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as described in claim 1, characterized in that, The weight ratio of sodium bromfenac to moxifloxacin hydrochloride is 1:1 to 1:5; The weight ratio of sodium bromfenac to moxifloxacin hydrochloride is 1:1, 1:2, 1:3, 1:4 or 1:

5.

4. The gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as described in claim 1, characterized in that, The osmotic pressure regulator is selected from one or more of sorbitol, glycerol, propylene glycol, and mannitol.

5. A method for preparing a gel eye drop containing bromfenac sodium and moxifloxacin hydrochloride as described in any one of claims 1 to 4, characterized in that, Includes the following steps: (1) Dissolve the gel matrix and sodium hyaluronate in a portion of purified water, allow them to swell fully, and sterilize at high temperature to obtain a gel matrix dispersion; (2) Dissolve sodium bromfenac and moxifloxacin hydrochloride in part of purified water, then add citric acid, sodium citrate and osmotic pressure regulator, stir evenly, filter to remove bacteria, and obtain the second solution; (3) Mix the second solution obtained in step (2) with the gel matrix dispersion obtained in step (1), add purified water to the required amount, stir, and fill into a single-dose packaging container.

6. The preparation method according to claim 5, characterized in that, In step (1), the high temperature is 120-130℃.

7. The preparation method according to claim 5, characterized in that, In step (2), a 0.22μm PVDF filter membrane is used for sterilization.

8. The preparation method according to claim 5, characterized in that, In step (3), the stirring speed is 1000-2000 rpm, the stirring temperature is 30-40℃, and the stirring time is 30-40 min.

9. The preparation method according to claim 5, characterized in that, In step (3), the filling volume is 0.4ml to 1.5ml.

10. The use of the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride as described in any one of claims 1 to 4, or the gel eye drops containing bromfenac sodium and moxifloxacin hydrochloride prepared by the preparation method described in any one of claims 5 to 9, in the preparation of anti-inflammatory drugs.

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