Levofloxacin eye drops and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of levofloxacin eye drops. Aiming at the problems of drug agglomeration, insufficient crystallization control, asepsis monitoring lagging, poor clinical administration suitability and the like of the levofloxacin eye drops, the invention provides a crystal inhibition process of step-by-step vacuum charging and programmed cooling coupled variable-frequency stirring, so that the dissolution uniformity and the physical stability are improved; the risk of dynamically intercepting particles, turbidity and main drug content is monitored on line through sterile filtration triple; the pre-nitrogen-filling ultraviolet blocking silicification bottle body is combined with the titanium alloy spring dropper, so that the chemical stability and the dropping amount consistency are guaranteed; and a stepped medication instruction for bacterial conjunctivitis and keratohelcosis and a morning and night time-sharing combined medication scheme are configured, so that full-chain optimization of production controllability, storage stability and treatment accuracy is realized.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly to levofloxacin eye drops and a preparation method thereof. Background Art

[0002] Levofloxacin, a third-generation fluoroquinolone antibacterial drug, is widely used to treat ocular infections such as bacterial conjunctivitis and corneal ulcers due to its broad-spectrum antibacterial activity and good tissue penetration. Eye drops, its mainstream dosage form, must balance sterility, stability, and ocular comfort, but existing production processes and formulation designs still have significant flaws.

[0003] The shortcomings of the existing technology are mainly reflected in the following aspects:

[0004] 1. Low drug dissolution efficiency and easy to agglomerate

[0005] The traditional process of adding the raw material at one time easily leads to the aggregation of micronized levofloxacin particles, forming insoluble clumps, which not only prolongs the dissolution time but also may cause uneven content and affect bioavailability.

[0006] 2. Insufficient crystallization risk control

[0007] The cooling process of conventional eye drops lacks refined temperature control and physical field assistance. Drug molecules are prone to disordered crystallization during the cooling stage, resulting in increased solution turbidity and excessive visible foreign matter. In particular, the stability is significantly reduced in high-altitude cold environments.

[0008] 3. Sterility assurance system lags behind

[0009] Existing filtration processes mostly rely on terminal membrane filtration and lack real-time quality monitoring methods throughout the entire production process. It is difficult to dynamically capture the risks of particulate generation, abnormal turbidity or degradation of the main drug, which increases the blind spots in sterility assurance.

[0010] 4. Lack of precision in clinical medication

[0011] The instructions for commercially available products usually only provide a general frequency of use, and do not design differentiated dosing strategies for different types of infections (such as conjunctivitis and corneal ulcers) or special populations (such as diabetic patients). They also do not integrate the timing management of combined drug use, resulting in limited efficacy.

[0012] Therefore, in response to the above problems, a levofloxacin eye drop and a preparation method thereof are proposed. Summary of the Invention

[0013] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present invention provide a levofloxacin eye drop and a preparation method thereof to solve the problems raised in the above-mentioned background technology.

[0014] To achieve the above object, the present invention provides the following technical solution: a method for preparing levofloxacin eye drops, characterized in that the following steps are performed in sequence:

[0015] S1. Inject 70-80% of the prescribed volume of water for injection into a closed dispensing system, heat to 50±1°C, add disodium EDTA, and stir at 350±50 rpm for 15 minutes.

[0016] S2. Add micronized levofloxacin via a vacuum feeder in four batches, with a 3-minute interval between each batch, wherein the levofloxacin D90 particle size is ≤5 μm;

[0017] S3. Add sodium chloride and premixed boric acid - borax powder, maintain temperature and stirring for 25 minutes;

[0018] S4. Start the cooling program: cool down from 50°C to 40°C at a rate of 0.8°C / min, and then to 25°C at a rate of 1.2°C / min. Apply variable frequency stirring throughout the cooling process, with stirring speeds of 250 rpm in the 50-40°C stage, 400 rpm in the 40-30°C stage, and 300 rpm in the 30-25°C stage.

[0019] S5. Adjust the pH to 5.5 ± 0.05 with 0.1 M HCl or 0.1 M NaOH solution under online pH monitoring;

[0020] S6. Add water for injection to the full volume and sterile filter through a 0.45 μm nylon filter and a 0.22 μm polyethersulfone filter in series at 0.28 MPa.

[0021] S7. Fill into pre-filled nitrogen eye drop bottles in an isolator with an oxygen content of ≤ 0.1%.

[0022] Furthermore, the components used in step S1 include 0.1-0.5% of levofloxacin, 0.5-0.9% of sodium chloride, 0.01-0.05% of disodium edetate, and 0.5-2.0% of boric acid-borax complex in terms of weight volume percentage concentration, and the boric acid and borax are premixed in a mass ratio of 1:0.8 to 1:1.2.

[0023] Furthermore, in step S6, the sterile filtration system simultaneously implements triple online monitoring, including a laser particle counter to monitor the number of particles with a particle size of ≥0.5 μm in real time, an optical fiber sensor to continuously detect the turbidity of the solution, and a near-infrared spectrometer to scan the levofloxacin content every 5 seconds.

[0024] Furthermore, during the cooling process in step S4, an ultrasonic field with a frequency of 40 kHz and a power of 50 W is applied to the solution in the temperature range of 25-40°C.

[0025] Furthermore, the pre-filled nitrogen eye drop bottle described in step S7 is a Class A brown neutral glass bottle that has been surface-siliconized and composited with an ultraviolet absorption coating, wherein the transmittance of the ultraviolet absorption coating in the wavelength range of 280-400nm is ≤3%, the bottle is pre-filled with 99.99% high-purity nitrogen so that the headspace oxygen content is ≤0.3%, and the bottle mouth is equipped with a titanium alloy spring-controlled dripper to achieve a dosing accuracy of 30±2μL / drop.

[0026] Furthermore, the method also includes the steps of configuring a medication regimen: for bacterial conjunctivitis, the medication instruction is to administer 1 drop 4 times a day; for corneal ulcer, the medication instruction is to administer 1 drop every 30 minutes within the first 48 hours and 1 drop every 2 hours after 48 hours.

[0027] Furthermore, the medication regimen configuration step further includes a combined medication instruction, specifying that the levofloxacin eye drops prepared by this method be used in the morning and the recombinant human epidermal growth factor eye drops be used at night, and the administration interval between the two eye drops be ≥30 minutes.

[0028] Technical effects and advantages of the present invention:

[0029] 1. Mechanism of improving drug dissolution and stability

[0030] By combining batch vacuum feeding operations with gradient temperature-controlled dissolution technology, the gradual dispersion of micronized drugs is achieved, effectively suppressing particle agglomeration. Simultaneously, variable frequency stirring during programmed cooling and synergistic intervention of ultrasonic fields are utilized to precisely control the crystallization kinetics of drug molecules, essentially improving the physical stability of the solution.

[0031] 2. Dynamic sterile quality assurance system

[0032] The innovative sterile filtration system with triple online monitoring is used to build a dynamic risk interception mechanism covering particulate control, solution clarity and chemical stability through laser particle monitoring, real-time turbidity detection and synchronous scanning of main drug content, thus completely eliminating the quality blind spots of traditional terminal filtration.

[0033] 3. Stability enhancement design of composite packaging

[0034] Through the synergistic effect of pre-filled nitrogen replacement and UV blocking coating, oxygen-sensitive degradation pathways and light-induced reactions are blocked; surface siliconization treatment significantly reduces drug adsorption loss, and combined with the mechanical control design of the titanium alloy spring dripper, dual guarantees of drug delivery accuracy and chemical stability are achieved.

[0035] 4.Technology integration for clinical precision drug delivery

[0036] Based on the differentiated medication instruction design based on the infection type, a stepped dosing regimen is configured for bacterial conjunctivitis and corneal ulcer respectively; through the timing management specifications of combined medication (such as the time-sharing strategy of morning antibacterial and nighttime repair), the therapeutic synergistic effect is maximized.

[0037] 5. Full-chain closed-loop optimization plan

[0038] From raw material dispersion control, crystallization inhibition process, online quality interception, to packaging stability enhancement and clinical drug administration adaptation, a systematic solution covering production preparation, quality control management, and clinical application is formed to comprehensively overcome the defects of traditional eye drops in process controllability, storage stability and treatment accuracy. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is the overall process flow chart of the present invention.

[0040] Figure 2 It is the program cooling control diagram of the present invention.

[0041] Figure 3 This is the clinical medication management diagram of the present invention. DETAILED DESCRIPTION

[0042] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Example 1:

[0043] Implementation process 1: Basic industrial production (focusing on process control)

[0044] Applicable scenario: GMP certified eye drops production line, annual output of 5 million units

[0045] Step 1: Raw material pretreatment and system startup

[0046] Into the 500L closed liquid preparation tank after CIP / SIP cleaning and sterilization, inject water for injection (about 400L) accounting for 80% of the total prescription. Start the heat exchange system to raise the water temperature to 50.0±0.5℃ (real-time temperature sensor monitoring), and add 30g of metal ion chelating agent disodium ethylenediaminetetraacetic acid (EDTA-2Na) (concentration 0.03% w / v). Turn on the double-layer turbine stirring paddle, set the speed to 350rpm and continue for 15 minutes until the solution is clear and free of suspended matter. The key control point at this stage is conductivity detection (≤2μS / cm) to ensure that there are no metal ions remaining.

[0047] Step 2: Dissolve the main drug step by step

[0048] 300g (0.3% w / v) of jet-milled levofloxacin (D90 = 4.3μm as measured by a Malvern laser particle size analyzer) was added in four batches of 75g each, spaced 3 minutes apart, via a vacuum feeding system. The next batch was added after the previous one was completely dissolved (visibly transparent and pale yellow). The temperature was maintained at 50±1°C, and the stirring speed was adjusted to 300rpm to minimize bubble generation. This procedure prevented drug powder agglomeration and shortened dissolution time by 40% compared to a single batch.

[0049] Step 3: Buffer system construction and cooling start

[0050] Add 75g of sodium chloride (0.75% w / v), an osmotic pressure regulator, and 120g of premixed boric acid-borax powder (mass ratio 1:1) (60g of boric acid + 60g of borax). Maintain stirring for 25 minutes and then start the cooling process:

[0051] Stage 1: 50°C → 40°C (rate 0.8°C / min), stirring speed increased to 400 rpm to enhance mass transfer

[0052] Second stage: 40℃→30℃ (rate 1.2℃ / min), stirring reduced to 300rpm to prevent bubbles

[0053] The third stage: 30℃→25℃ (rate 1.0℃ / min), stirring maintained at 300rpm

[0054] The temperature is controlled by jacket cooling water circulation throughout the process, with a temperature deviation of ≤0.3℃.

[0055] Step 4: pH precision control and filtration

[0056] Connect an online pH sensor (Mettler T-type electrode) and automatically titrate 0.1M NaOH solution to adjust the pH from the initial 6.8 to 5.52±0.03 (regulation takes 8 minutes). Add injection water to a total volume of 500L and start serial filtration:

[0057] Pre-filtration: 0.45μm nylon membrane (retains particles ≥10μm)

[0058] Sterile filtration: 0.22μm PES membrane (pressure 0.28MPa)

[0059] The triple monitoring system operates in real time: a laser particle counter (alarm value for particles >0.5μm: 50 particles / mL), a fiber optic turbidity meter (threshold: 0.5NTU), and a near-infrared spectrometer (automatic diversion when the main drug content deviation is >1%).

[0060] Step 5: Ultra-low oxygen filling and packaging

[0061] In a nitrogen-filled isolator (oxygen content 0.08%), the liquid medicine is filled into pre-treated Grade A brown glass bottles:

[0062] Bottle treatment: Surface silanization to prevent adsorption, coated with benzotriazole UV coating (380nm transmittance 2.3%)

[0063] Nitrogen filling: The bottle is pre-filled with 99.99% nitrogen (headspace oxygen 0.22%)

[0064] Filling: Peristaltic pump quantitative filling 3.00±0.03g / bottle (electronic balance feedback control)

[0065] Dripper assembly: Titanium alloy spring controls the dripping volume (32.5±0.7μL / drop), caps are screwed on immediately after filling, and products with deviations greater than 0.5% are rejected through online weight check.

[0066] Implementation process 2: Ultrasonic enhanced anti-crystallization process (focusing on physical stability)

[0067] Applicable scenarios: transporting products in cold regions, which need to withstand freeze-thaw cycles at -20°C

[0068] Step 1: Buffer system pre-activation

[0069] Place 60g of boric acid and 60g of borax in a three-dimensional motion mixer and mix at 25 rpm for 30 minutes. Dissolve a small amount of the mixture in 50°C water and verify that the pH is 7.01 (the characteristic value for an equimolar ratio of boric acid and borax) to confirm that the buffer capacity is acceptable. This premixing procedure ensures a uniform distribution of buffer ions and improves pH stability by 17% compared to fresh mixing.

[0070] Step 2: Ultrasonication-assisted dissolution

[0071] During the addition of levofloxacin in step S3, a 40kHz ultrasonic generator was activated: the titanium alloy probe was immersed 5cm below the liquid surface and the power was set to 50W for continuous transmission. Ultrasonic cavitation caused the drug molecules to form a metastable complex [levofloxacin·3H2O] with water. Raman spectroscopy confirmed that the hydration bond strength increased by 2.1 times.

[0072] Step 3: Gradient cooling coupled with ultrasonic field

[0073] Ultrasonic waves were applied throughout the cooling process of the S4 program, with a focus on controlling the phase transition risk zone: in the 40-35°C range, the ultrasonic power was increased to 60W (high-risk crystallization nucleation zone); in the 30-25°C range, the ultrasonic power was maintained at 50W (crystal growth inhibition zone);

[0074] DSC detection showed that the crystallization starting temperature dropped to 4.2°C (18.5°C in conventional process), and the supersaturation of the solution increased to above the safety threshold.

[0075] Step 4: Freeze-thaw filtration process

[0076] After completing S6 filtration, perform a deep cooling test: freeze 100 mL of the filtrate at -20°C for 24 hours, warm it to 25°C, and filter it a second time through a 0.45 μm membrane (to retain potential crystallites). Near-infrared spectroscopy confirms a resolubility rate >99.9%, ensuring that no residual crystals remain after freeze-thaw cycles.

[0077] Step 5: Cold-resistant packaging verification

[0078] After filling, sample the product and perform three freeze-thaw cycles (-20℃ / 24h→25℃ / 8h). Open the bottle and check: turbidity ≤0.8NTU (scattering method) >10μm; particles ≤6 / mL (flow imaging); pH deviation ≤0.15

[0079] Products that meet the standards will be affixed with the "Cold-Resistant Transportation" logo.

[0080] Implementation Process 3: Integrated Clinical Treatment Program (Focus on Medication Management)

[0081] Applicable scenarios: hospital pharmacy services, combined treatment of diabetic corneal ulcers

[0082] Step 1: Customized packaging

[0083] Levofloxacin eye drops are packaged into dedicated treatment bags in a Class B clean room:

[0084] Conjunctivitis kit: 7 single-dose eye drops (0.4 mL / tube), labeled "4 times daily";

[0085] Corneal ulcer kit: Contains 48 hourly vials (0.25 mL / vial) + 14 daily vials (0.5 mL / vial); each vial is marked with the medication time window (e.g., hourly vial printed with "Day 1-2: q30 min");

[0086] Step 2: Smart medication reminder system

[0087] Scan the QR code on the medicine box to activate the APP service:

[0088] Conjunctivitis mode: daily vibration reminder at 8:00 / 12:00 / 16:00 / 20:00;

[0089] Corneal ulcer pattern:

[0090] First 48 hours: Ring tone every 30 minutes (6:00-22:00);

[0091] Later period: reminder every 2 hours (7:00-23:00);

[0092] After using the medicine, you need to scan the dripper to confirm the execution.

[0093] Step 3: Sequential combination medication

[0094] Patients with diabetic corneal ulcers should undergo morning and evening treatment:

[0095] Morning antibacterial: After cleaning your hands, pull open the lower eyelid and instill levofloxacin eye drops (prepared in this patent) into the conjunctival sac (1 drop / time), pressing the lacrimal sac area for 1 minute to reduce systemic absorption;

[0096] Nighttime repair: Use recombinant human epidermal growth factor (rhEGF) at least 30 minutes before bedtime. Close your eyes and rotate them after instillation to promote distribution.

[0097] It is strictly forbidden to mix two eye drops.

[0098] Step 4: Closed-loop feedback loop

[0099] Patients upload eye photos to the medical platform every day:

[0100] AI analysis module: conjunctival congestion area (OpenCV image recognition), corneal ulcer diameter (pixel scale conversion);

[0101] Pharmacist intervention threshold:

[0102] If inflammation does not subside within 48 hours: escalate to q15min dosing

[0103] On the 5th day, if the wound surface is reduced by <30%, a multidisciplinary consultation is initiated and the system automatically generates a medication compliance report (compliance rate >93%).

[0104] Finally, a few points should be explained: First, in the description of this application, it should be noted that, unless otherwise specified or limited, the terms "mounted," "connected," and "connected" should be understood in a broad sense, and may refer to mechanical or electrical connections, internal communication between two components, or direct connection. "Up," "down," "left," and "right" are only used to indicate relative positional relationships. When the absolute positions of the objects being described change, the relative positional relationships may also change.

[0105] Secondly: The drawings of the embodiments disclosed in the present invention only involve structures related to the embodiments disclosed in the present invention. Other structures may refer to conventional designs. The same embodiment and different embodiments of the present invention may be combined with each other without conflict.

[0106] Finally: The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing levofloxacin eye drops, characterized in that Follow these steps in order: S1. Inject 70-80% of the prescribed volume of water for injection into a closed dispensing system, heat to 50±1°C, add disodium EDTA, and stir at 350±50 rpm for 15 minutes. S2. Add micronized levofloxacin via a vacuum feeder in four batches, with a 3-minute interval between each batch, wherein the levofloxacin D90 particle size is ≤5 μm; S3. Add sodium chloride and premixed boric acid - borax powder, maintain temperature and stirring for 25 minutes; S4. Start the cooling program: cool down from 50°C to 40°C at a rate of 0.8°C / min, and then to 25°C at a rate of 1.2°C / min. Apply variable frequency stirring throughout the cooling process, with stirring speeds of 250 rpm in the 50-40°C stage, 400 rpm in the 40-30°C stage, and 300 rpm in the 30-25°C stage. S5. Adjust the pH to 5.5 ± 0.05 with 0.1 M HCl or 0.1 M NaOH solution under online pH monitoring; S6. Add water for injection to the full volume and sterile filter through a 0.45 μm nylon filter and a 0.22 μm polyethersulfone filter in series at 0.28 MPa. S7. Fill into pre-filled nitrogen eye drop bottles in an isolator with an oxygen content of ≤ 0.1%.

2. A method for preparing levofloxacin eye drops according to claim 1, characterized in that: The components used in step S1 include 0.1-0.5% of levofloxacin, 0.5-0.9% of sodium chloride, 0.01-0.05% of disodium edetate, and 0.5-2.0% of a boric acid-borax complex in terms of weight volume percentage concentration, and the boric acid and borax are premixed in a mass ratio of 1:0.8 to 1:1.

2.

3. A method for preparing levofloxacin eye drops according to claim 1 or 2, characterized in that: In step S6, the sterile filtration system simultaneously implements triple online monitoring, including a laser particle counter to monitor the number of particles with a particle size of ≥0.5 μm in real time, an optical fiber sensor to continuously detect the turbidity of the solution, and a near-infrared spectrometer to scan the levofloxacin content every 5 seconds.

4. A method for preparing levofloxacin eye drops according to any one of claims 1 to 3, characterized in that: During the cooling process in step S4, an ultrasonic field with a frequency of 40 kHz and a power of 50 W is applied to the solution in the temperature range of 25-40°C.

5. A method for preparing levofloxacin eye drops according to any one of claims 1 to 4, characterized in that: The pre-filled nitrogen eye drop bottle described in step S7 is a Class A brown neutral glass bottle with a siliconized surface and a composite ultraviolet absorption coating, wherein the transmittance of the ultraviolet absorption coating in the wavelength range of 280-400nm is ≤3%, the bottle is pre-filled with 99.99% high-purity nitrogen so that the headspace oxygen content is ≤0.3%, and the bottle mouth is equipped with a titanium alloy spring-controlled dripper to achieve a dosing accuracy of 30±2μL / drop.

6. The method for preparing levofloxacin eye drops according to any one of claims 1 to 5, wherein the method is characterized in that It also includes the steps of configuring the medication regimen: for bacterial conjunctivitis, the medication instructions are to administer 1 drop 4 times a day; for corneal ulcers, the medication instructions are to administer 1 drop every 30 minutes for the first 48 hours and 1 drop every 2 hours after 48 hours.

7. A method for preparing levofloxacin eye drops according to claim 6, characterized in that: The medication regimen configuration step further includes a combined medication instruction, specifying that the levofloxacin eye drops prepared by this method be used in the morning and the recombinant human epidermal growth factor eye drops be used at night, and the administration interval between the two eye drops be ≥30 minutes.

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