Ribavirin spray and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly discloses a ribavirin spray and a preparation method thereof. The method comprises the following core steps: pre-treating raw materials and auxiliary materials in a D-grade clean area; a step-by-step process of firstly dissolving auxiliary materials and then adding raw materials is adopted in the C-grade clean area to prepare liquid medicine; enabling the liquid medicine to pass through a three-stage filtration system comprising rough filtration, fine filtration and terminal sterilization filtration, and hermetically transferring the liquid medicine to a B-stage clean area under positive pressure; and finally, carrying out sterile filling and sealing in an A-grade laminar flow protection environment under a B-grade background, and carrying out sealing integrity and spraying performance detection on a finished product. According to the invention, the ribavirin spray which is uniform in spray particle size, accurate in administration dosage and high in sterility assurance level can be stably produced by constructing a graded clean production process, accurately controlling key process parameters and implementing quality monitoring in the whole process, and meanwhile, high efficiency and energy conservation of the production process are realized.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, and more specifically, to a ribavirin spray and a method for preparing the same. Background Technology

[0002] Ribavirin, a broad-spectrum antiviral drug, effectively inhibits the replication of various viruses that cause upper respiratory tract infections, such as respiratory syncytial virus, influenza virus, and adenovirus. It is currently widely used in the treatment of viral pharyngitis, rhinitis, herpetic pharyngitis, and hand-foot-and-mouth disease. Compared to traditional oral or intravenous administration, nebulizers deliver the drug directly to the respiratory tract lesions, offering significant advantages such as rapid onset of action, high local drug concentration, and fewer systemic side effects. It is particularly suitable for patients with poor tolerance to systemic medications, such as children and the elderly. Therefore, the clinical demand for ribavirin nebulizers remains stable.

[0003] In existing production technologies, the preparation of ribavirin spray typically involves multiple steps, including weighing, dissolving, mixing, filtering, filling, and sealing of raw materials and excipients. Although some processes have attempted to improve efficiency by using premixed excipients and simplifying operational procedures, several key technological bottlenecks still exist in actual industrial production, affecting the product's quality stability, safety, and production efficiency. These bottlenecks manifest in the following ways:

[0004] Existing processes often lack clear and standardized control over key process parameters such as material mixing speed, stirring time, filtration pressure, and filling accuracy. This extensive production process easily leads to fluctuations in the uniformity of drug content across different batches and inconsistent spray particle size distribution. When the particle size is too large, the droplets cannot effectively adhere to the mucous membrane surface; when the particle size is too small, they are easily inhaled into the trachea, both of which affect the effective deposition and efficacy of the drug. At the same time, some processes lack real-time or timed monitoring of key quality attributes of intermediate products (such as drug solutions) (such as pH value, clarity, and complete dissolution), which may lead to insufficient dissolution of raw materials or residual impurities, further reducing the quality stability of the final product and making it difficult to meet the clinical requirements for precise dosage.

[0005] Existing technologies have deficiencies in the design and management of clean areas in production environments. On the one hand, some processes fail to rationally classify cleanliness levels according to the contamination risk of different procedures. For example, drug preparation and filling may be carried out simultaneously in a Class D clean area with lower cleanliness, or although different cleanliness levels are set up, effective sealing measures are lacking during material transfer, increasing the risk of microbial and dust particle contamination and potentially leading to products exceeding microbial limits. On the other hand, some overly simplified processes attempt to complete production entirely within a Class D clean area, but their cleanliness cannot fully meet the standards for formulation production with high aseptic or microbial control requirements, creating safety hazards and affecting medication safety.

[0006] Some existing processes still involve cumbersome steps such as separate dissolution of excipients and multiple non-sealed transfers, leading to extended production cycles and low efficiency. Furthermore, the compatibility between the process flow and production equipment has not been fully optimized, resulting in poor coordination between different processes and unnecessary energy and material waste. This not only contradicts the trend of the pharmaceutical manufacturing industry towards "high efficiency, energy saving, and low carbon emissions," but also increases the production and operating costs of enterprises.

[0007] Therefore, there is an urgent need to develop a new method for preparing ribavirin spray to overcome the above-mentioned defects of existing technologies, achieve the comprehensive goals of stable and controllable product quality, safe and standardized production process, and efficient and energy-saving process flow, thereby providing a high-quality ribavirin spray product that better meets clinical needs. Summary of the Invention

[0008] To address the aforementioned issues, this application provides a ribavirin spray and a method for preparing the same.

[0009] The technical solution adopted in this application is as follows:

[0010] In a first aspect, this application provides a method for preparing ribavirin spray, comprising:

[0011] (1) In a Class D clean environment, weigh the ribavirin raw material and excipients and sieve them;

[0012] (2) In a Class C clean environment, the excipients are dissolved in part of purified water, then the ribavirin raw material is added and stirred to dissolve, and purified water is added to the total volume to obtain the drug solution;

[0013] (3) After the drug solution is passed through a three-stage filtration system of coarse filtration, fine filtration and sterile terminal filtration, it is transferred in a sealed manner to a sterile storage tank in a Class B clean area.

[0014] (4) Under the conditions of a Class B clean environment and Class A laminar flow protection at the filling site, the medicine liquid in the sterile storage tank is filled into a sterilized spray bottle and sealed immediately;

[0015] (5) Test the seal integrity and spray performance of the sealed spray bottle.

[0016] Further, in step (1), the excipients include at least a solubilizer, a preservative and a humectant; the ribavirin raw material is sieved through a 100-mesh sieve, and the solid components in the excipients are sieved through an 80-mesh sieve.

[0017] Preferably, the solubilizer is hydroxypropyl-β-cyclodextrin, the preservative is benzalkonium chloride, and the humectant is glycerin.

[0018] Preferably, during the precise weighing of ribavirin raw materials (purity ≥99.5%) and excipients according to the prescription ratio, the weighing error is controlled within ±0.5%. The raw materials are sieved through a 100-mesh sieve to remove any possible lumps and impurities; solid components in the excipients (such as hydroxypropyl-β-cyclodextrin) are sieved through an 80-mesh sieve to ensure uniform dissolution in the subsequent process.

[0019] Furthermore, step (2) specifically includes:

[0020] At a temperature of 33-37℃, the solubilizer, preservative and humectant are first added to purified water at 70%-90% of the prescription amount, and stirred at 250-350 r / min for 10-20 min until completely dissolved;

[0021] Add ribavirin raw material, keep stirring, and continue to dissolve for 20-40 minutes. During this period, observe the clarity of the solution in real time through an online monitoring system.

[0022] Add purified water to the full prescription volume, stir and mix well, and then test the pH value and content uniformity of the solution.

[0023] In the above technical solution, by dissolving excipients and raw materials in stages, combined with appropriate temperature and stirring parameters, all components are fully dissolved to avoid excessively high local concentrations or undissolved particles remaining; real-time monitoring of pH value and content uniformity ensures that the core indicators of the drug solution meet the quality requirements of intermediate products and prevents unqualified drug solutions from entering subsequent processes.

[0024] The process of "dissolving in warm water at 33~37℃ + step-by-step feeding" can increase the dissolution rate of ribavirin raw materials by more than 30% compared with the existing technology of one-time feeding at room temperature (around 25℃), shorten the stirring time, reduce the agglomeration of raw materials, and improve the uniformity of the drug solution. The introduction of an online monitoring system to observe the clarity in real time, combined with sampling to test the pH value and content uniformity, forms a dual control of "real-time monitoring + sampling verification". Compared with the existing technology that only conducts end-point sampling testing, it can detect problems such as incomplete dissolution and ratio deviation more promptly, and reduce the rate of defective products.

[0025] Furthermore, the three-stage filtration system described in step (3) includes:

[0026] The first stage of filtration is coarse filtration using a 3~7μm pleated filter element;

[0027] The second stage of filtration is fine filtration using a 0.4~0.5μm filter element;

[0028] The third stage of filtration is terminal sterilization filtration using a 0.2~0.25μm sterile filter cartridge;

[0029] During the closed transfer process, the pressure inside the pipeline is maintained at 0.3-0.5 MPa.

[0030] Furthermore, during the treatment process of the three-stage filtration system, the temperature of the drug solution is controlled at 20-25℃ throughout the process; after filtration, the drug solution is tested for microbial limits and visible foreign matter, and only after passing the tests can it be temporarily stored in the sterile storage tank.

[0031] The above technical solution utilizes a three-stage filtration system of "coarse filtration - fine filtration - sterile terminal filtration" to thoroughly remove impurities and microorganisms from the drug solution, ensuring its sterility and clarity. The closed transfer and filtration process prevents secondary contamination of the drug solution during its journey across clean areas.

[0032] The system employs a three-stage progressive filtration process: coarse filtration, fine filtration, and sterile terminal filtration. Compared to existing 2-3 stage filtration technologies (such as only 0.45μm + 0.22μm), it can more efficiently intercept impurities of different particle sizes, reduce terminal filter clogging, extend filter life, and lower production costs. During the filtration process, the system controls pipeline pressure and drug solution temperature to prevent pressure fluctuations from causing filter breakage and excessively high temperatures from affecting drug stability, ensuring that the sterility and efficacy of the filtered drug solution are not affected.

[0033] Furthermore, in step (4), the spray bottle is sterilized at 110~130℃ for 20~40min and then cooled in a Class A laminar flow environment; the error of the filling amount is controlled within ±1%; during the filling process, the wind speed of the Class A laminar flow is 0.36-0.54 m / s.

[0034] The above technical solution completes filling and sealing under Class A laminar flow protection, minimizing the risk of contamination of the product by environmental microorganisms and dust particles; it precisely controls the filling volume to ensure that the drug content of each bottle is consistent, and the sealing operation ensures the sterility and efficacy stability of the product during its shelf life.

[0035] Employing a dual cleanroom protection system of "Class B clean area + Class A laminar flow," compared to existing technologies that only use a Class B clean area for filling, the risk of environmental microbial contamination can be reduced by more than 90%, and the product sterility qualification rate can be increased to over 99.9%. The high-frequency testing during the filling process—checking accuracy every 50 bottles + checking for microorganisms every 100 bottles—compared to existing technologies that only perform end-of-batch testing, can promptly detect issues such as filling equipment deviations and fluctuations in environmental cleanliness, preventing the generation of batches of substandard products. The spray bottles and nozzles are simultaneously sterilized before being directly used in the Class A laminar flow area, avoiding the problem of "secondary contamination during the transfer process after sterilization" in existing technologies, further ensuring product sterility.

[0036] Furthermore, in step (5), the seal integrity test adopts the vacuum decay method, which maintains a vacuum condition of -0.07 to -0.09 MPa for 20 to 40 seconds, and the pressure change value is ≤0.005 MPa to be considered qualified.

[0037] Furthermore, the spray performance test includes the detection of spray particle size, spray uniformity, and content per spray. The spray particle size is controlled within 10~50μm, the coefficient of variation of spray uniformity is ≤10%, and the content deviation per spray is ≤±5%, which is considered as qualified.

[0038] By testing the seal integrity, we ensure that the product is leak-free and avoid microbial invasion within the expiration date, which could lead to efficacy reduction or contamination. We also test the spray performance to ensure that the product sprays smoothly and with appropriate particle size during use, so that it can accurately adhere to the nasal cavity and pharyngeal mucosa and ensure efficacy.

[0039] The vacuum attenuation method is used to detect seal integrity, which improves the detection accuracy by more than 5 times compared to the traditional method of "immersing in water to observe bubbles". It can detect tiny leaks (leaks ≤1μm) and has no risk of secondary water contamination. The detection efficiency is increased by 2 times. The spray particle size is clearly controlled at 10-50μm (suitable for the adhesion of nasal and pharyngeal mucosa) and the content deviation of each spray is detected. Compared with the existing technology that only detects "whether it can be sprayed", it can more accurately ensure the product's effectiveness, ensure consistent spray performance across different batches, and improve the medication experience.

[0040] Secondly, this application provides a ribavirin spray, which is prepared by the above-described preparation method.

[0041] In summary, this application has the following beneficial effects:

[0042] The ribavirin spray preparation method provided by this invention, through systematic process design, effectively overcomes the defects of the prior art, such as uneven quality, safety risks and low efficiency, and achieves significant comprehensive benefits.

[0043] Firstly, regarding improving product quality and uniformity, this invention precisely controls key process parameters such as raw material sieve mesh size, drug solution preparation temperature, stirring speed, and time. It also establishes a three-stage filtration system encompassing coarse filtration, fine filtration, and terminal sterilization filtration, ensuring complete dissolution of active ingredients, physicochemical stability of the solution, and extremely high clarity. This results in minimal deviation in drug content uniformity in the final product, precise control of spray particle size within the ideal range of 10-50 μm, and high spray uniformity. This guarantees accurate dosage and reliable efficacy for clinical administration, solving the problems of inconsistent spray performance and unstable drug efficacy caused by ambiguous parameters in traditional processes.

[0044] Secondly, regarding ensuring product safety and aseptic reliability, this invention innovatively adopts a cleanroom zoning strategy based on process risk classification, namely "Level D pretreatment—Level C preparation—Level B storage and filtration—Level A laminar flow filling (under Level B background)". This strategy ensures a close match between the cleanliness of the production environment and the contamination risk of each operational step. Combined with positive pressure closed-loop transfer via pipelines, terminal sterilization filtration, and Level A unidirectional flow protection in the filling process, a comprehensive microbial and particulate contamination control system is constructed, fundamentally reducing the risk of product contamination and significantly improving aseptic assurance levels. This is particularly suitable for respiratory direct-drug formulations with extremely high safety requirements.

[0045] Finally, in terms of optimizing production efficiency and controllability, this invention efficiently connects the steps of excipient dissolution, active pharmaceutical ingredient addition, and three-stage filtration within a continuous cleanroom sequence, reducing unnecessary intermediate transfers and waiting times. All critical operating points (such as filtration pressure, filling accuracy, and laminar flow velocity) and key quality attributes (such as content, pH, particle size, and sealing performance) in the process have clearly defined quantitative control standards and online / offline detection nodes. This standardized and parameterized design not only significantly improves production efficiency and process reproducibility between different batches, and reduces energy consumption and material loss, but also achieves dual verification of the finished product's sealing integrity and spray functionality by introducing advanced quality control methods such as vacuum decay leak detection, providing a solid guarantee for stable industrial production and high-quality release of the product. Attached Figure Description

[0046] Figure 1 This is a process flow diagram of the preparation of ribavirin spray provided in this application. Detailed Implementation

[0047] The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Specific conditions not specified in the examples shall be carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0048] The terms "Class B clean environment," "Class C clean environment," "Class D clean environment," and "Class A laminar flow" mentioned in this invention refer to the cleanliness levels of sterile drug production environments as stipulated in the National Medical Products Administration's "Good Manufacturing Practice for Pharmaceuticals" and its appendices. Specifically, "Class A laminar flow" refers to unidirectional airflow protection provided in critical operational areas (such as the filling area), with an air velocity typically maintained at 0.36-0.54 m / s (e.g., 0.45 m / s ± 20%).

[0049] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0050] Example 1

[0051] This embodiment provides a ribavirin spray, the process flow of which is as follows: Figure 1 As shown, the specific steps include:

[0052] (1) Pretreatment of raw materials and auxiliary materials

[0053] In a Class D clean area, accurately weigh 50.0g of ribavirin raw material, with the weighing error controlled between 49.75g and 50.25g; weigh 100.0g of hydroxypropyl-β-cyclodextrin, 5.0g of benzalkonium chloride, and 50.0ml of glycerin, with the weighing error of each excipient ≤ ±0.5%.

[0054] The weighed ribavirin raw material was sieved through a 100-mesh stainless steel sieve. The material was slowly poured out and the sieve was gently tapped to collect the sieved raw material. Any lumps and impurities remaining on the sieve were removed. Hydroxypropyl-β-cyclodextrin and benzalkonium chloride were sieved through an 80-mesh stainless steel sieve, and the excipients were collected in the same way.

[0055] The processed raw materials and auxiliary materials are placed separately into sealed PE material containers labeled with the material name, and placed on the material storage rack in the Class D clean area for later use, avoiding direct contact with the external environment.

[0056] (2) Preparation of drug solution

[0057] Transfer the spare auxiliary materials and raw materials from the Class D clean area to the Class C clean area through the transfer window. Pour 8000ml of purified water into the stainless steel sealed mixing tank, turn on the temperature control system, set the water temperature to 35℃, and when the water temperature stabilizes between 33℃ and 37℃, start the mixing device and set the mixing speed to 300r / min.

[0058] First, add 100.0g of sieved hydroxypropyl-β-cyclodextrin and 5.0g of benzalkonium chloride, then pour in 50.0ml of glycerol. Keep the stirring speed constant and stir for 15 minutes. Observe whether the excipients are completely dissolved and ensure that there are no visible particles remaining.

[0059] Slowly add 50.0g of sieved ribavirin raw material and continue stirring at 300r / min for 30 minutes. During this time, observe the clarity of the solution in real time through the online visual monitoring device built into the mixing tank. If undissolved particles are found in some areas, extend the stirring time by 5-10 minutes.

[0060] Add the remaining 2000ml of purified water to adjust the total volume of the solution to 10000ml. Stir for 5 minutes while maintaining the stirring speed to ensure the solution is evenly mixed.

[0061] Use a sterile sampler to extract 5ml of the drug solution and send it to the intermediate laboratory to test the pH value (standard range 5.0-7.0) and content uniformity (deviation ≤2%). After passing the test, temporarily store the drug solution in a mixing tank and keep it at a temperature of 20-25℃ for later use.

[0062] (3) Precision multi-stage filtration

[0063] Turn on the closed pipeline transport system between the Class C and Class B clean areas, set the pipeline pressure to 0.4 MPa, and transfer the qualified drug solution in the mixing tank to the sterile buffer tank in the Class B clean area through the closed pipeline. Monitor the pipeline pressure in real time during the transfer process to ensure that the pressure is stable between 0.3-0.5 MPa and avoid negative pressure aspiration of contaminants.

[0064] The filtration system is started, and the drug solution is first coarsely filtered through a 5μm pleated filter cartridge at a flow rate of 10 L / h to remove residual small insoluble impurities and colloidal particles. After coarse filtration, the system is switched to a 0.45μm polyethersulfone (PES) filter cartridge for fine filtration at a flow rate of 8 L / h to further intercept fine impurities and some microorganisms. Finally, the solution is filtered through a 0.22μm sterile filter cartridge at a flow rate of 6 L / h to achieve sterilization of the drug solution.

[0065] After filtration, the solution is temporarily stored in a sterile storage tank in a Class B clean area. The solution temperature is maintained at 20-25℃ throughout the process. 10ml of solution is extracted with a sterile sampler and tested for microbial limits (≤10 CFU / ml) and visible foreign matter (not detectable). If the test is qualified, it proceeds to the next process.

[0066] (4) Aseptic filling

[0067] Place the blank spray bottle (including the nozzle) into the tunnel sterilizer, set the sterilization parameters to 121℃ for 30 minutes. After sterilization, transfer the spray bottle into the Class A laminar flow workbench through the sealed transfer channel and cool it to room temperature (20-25℃).

[0068] The operator starts the quantitative filling pump in the Class A laminar flow workbench, sets the filling volume to 10ml / bottle, and controls the filling error between 9.9ml and 10.1ml.

[0069] Start the filling equipment and inject the liquid medicine in the sterile storage tank into the spray bottle through the filling pump. During the filling process, keep the air velocity of the Class A laminar flow workbench stable at 0.36-0.54 m / s to avoid airflow fluctuations that may cause contamination.

[0070] For every 50 bottles filled, one bottle is randomly selected and the filling volume is checked using a calibrated volumetric flask to ensure that the accuracy meets the requirements; for every 100 bottles filled, one bottle is randomly selected to test the microbial limit (sterility) of the liquid inside the bottle. If any non-compliance is found, the machine is immediately stopped and the cause is investigated.

[0071] After filling, under Class A laminar flow protection, each spray bottle is immediately capped and sealed with a pump to ensure a tight seal between the bottle and the spray nozzle, with no loosening.

[0072] (5) Seal integrity and spray performance testing

[0073] After sealing, the spray bottle is transferred to the vacuum decay test equipment in the Class B clean area. The spray bottle is placed in the test chamber, the vacuum degree is set to -0.08MPa, and it is maintained for 30 seconds. The equipment automatically records the pressure change inside the bottle. The pressure change value is ≤0.005MPa, which is considered qualified. Products with poor sealing that exceed the pressure change value are rejected.

[0074] The sealed and qualified products are transferred to the Class D clean area through the transfer window. 1% of the total product quantity of each batch is sampled (10 bottles are sampled for every 1000 bottles produced in this batch; if less than 20 bottles are produced, 20 bottles are sampled, and an additional 10 bottles are sampled). The sample is fixed on the spray performance testing device, the nozzle is started to spray, and the spray particle size (standard range 10-50μm), spray uniformity (coefficient of variation ≤10%), and content per spray (deviation ≤±5%) are tested. The test data are recorded.

[0075] Quality inspectors conduct visual inspections, checking whether the bottle is intact and undamaged, whether the nozzle is securely installed, whether the liquid is clear and free of visible foreign matter, and rejecting products that do not meet the appearance standards.

[0076] (6) Outer packaging and finished product warehousing

[0077] At the outer packaging station in the Class D clean area, operators affix outer labels to each qualified product that has passed all tests, ensuring that the labels are affixed in a uniform position (center of the bottle), flat, and without bubbles or curling edges.

[0078] The packaged finished products are transferred to the finished product warehouse and stored on the shelves according to batch number. The warehouse is maintained at a temperature and humidity of 15-25℃ and a relative humidity of 45%-65%. Good records of the goods entering the warehouse are kept.

[0079] Example 2

[0080] The difference between this embodiment and Example 1 lies in the preparation process of the drug solution:

[0081] Transfer the spare auxiliary materials and raw materials from the Class D clean area to the Class C clean area through the transfer window. Pour 7000ml of purified water into the stainless steel sealed mixing tank, turn on the temperature control system, set the water temperature to 35℃, and when the water temperature stabilizes between 33℃ and 37℃, start the mixing device and set the mixing speed to 250r / min.

[0082] First, add 100.0g of sieved hydroxypropyl-β-cyclodextrin and 5.0g of benzalkonium chloride, then pour in 50.0ml of glycerol. Keep the stirring speed constant and stir for 40 minutes. Observe whether the excipients are completely dissolved and ensure that there are no visible particles remaining.

[0083] Slowly add 50.0g of sieved ribavirin raw material and continue stirring at 250r / min for 35 minutes. During this time, observe the clarity of the solution in real time through the online visual monitoring device built into the mixing tank. If undissolved particles are found in some areas, extend the stirring time by 5-10 minutes.

[0084] Add the remaining 3000ml of purified water to adjust the total volume of the solution to 10000ml. Stir for 5 minutes while maintaining the stirring speed to ensure the solution is evenly mixed.

[0085] Use a sterile sampler to extract 5ml of the drug solution and send it to the intermediate laboratory to test the pH value (standard range 5.0-7.0) and content uniformity (deviation ≤2%). After passing the test, temporarily store the drug solution in a mixing tank and keep it at a temperature of 20-25℃ for later use.

[0086] Example 3

[0087] The difference between this embodiment and Example 1 lies in the preparation process of the drug solution:

[0088] Transfer the spare auxiliary materials and raw materials from the Class D clean area to the Class C clean area through the transfer window. Pour 9000ml of purified water into the stainless steel sealed mixing tank, turn on the temperature control system, set the water temperature to 35℃, and when the water temperature stabilizes between 33℃ and 37℃, start the stirring device and set the stirring speed to 350r / min.

[0089] First, add 100.0g of sieved hydroxypropyl-β-cyclodextrin and 5.0g of benzalkonium chloride, then pour in 50.0ml of glycerol. Keep the stirring speed constant and stir for 20 minutes. Observe whether the excipients are completely dissolved and ensure that there are no visible particles remaining.

[0090] Slowly add 50.0g of sieved ribavirin raw material and continue stirring at 300r / min for 20 minutes. During this time, observe the clarity of the solution in real time through the online visual monitoring device built into the mixing tank. If undissolved particles are found in some areas, extend the stirring time by 5-10 minutes.

[0091] Add the remaining 1000ml of purified water to adjust the total volume of the solution to 10000ml. Stir for 5 minutes while maintaining the stirring speed to ensure the solution is evenly mixed.

[0092] Use a sterile sampler to extract 5ml of the drug solution and send it to the intermediate laboratory to test the pH value (standard range 5.0-7.0) and content uniformity (deviation ≤2%). After passing the test, temporarily store the drug solution in a mixing tank and keep it at a temperature of 20-25℃ for later use.

[0093] Example 4

[0094] The difference between this embodiment and Embodiment 1 lies in the precision multi-stage filtration process:

[0095] Turn on the closed pipeline transport system between the Class C and Class B clean areas, set the pipeline pressure to 0.35 MPa, and transfer the qualified drug solution in the mixing tank to the sterile buffer tank in the Class B clean area through the closed pipeline. Monitor the pipeline pressure in real time during the transfer process to ensure that the pressure is stable between 0.3-0.4 MPa and avoid negative pressure aspiration of contaminants.

[0096] The filtration system is started, and the drug solution is first coarsely filtered through a 4μm pleated filter cartridge at a flow rate of 10 L / h to remove residual small insoluble impurities and colloidal particles. After coarse filtration, the system is switched to a 0.42μm polyethersulfone (PES) filter cartridge for fine filtration at a flow rate of 8 L / h to further intercept fine impurities and some microorganisms. Finally, the solution is filtered through a 0.22μm sterile filter cartridge at a flow rate of 6 L / h to achieve sterilization of the drug solution.

[0097] After filtration, the solution is temporarily stored in a sterile storage tank in a Class B clean area. The solution temperature is maintained at 20-25℃ throughout the process. 10ml of solution is extracted with a sterile sampler and tested for microbial limits (≤10 CFU / ml) and visible foreign matter (not detectable). If the test is qualified, it proceeds to the next process.

[0098] Example 5

[0099] The difference between this embodiment and Embodiment 1 lies in the aseptic filling process:

[0100] Place the blank spray bottle (including the nozzle) into the tunnel sterilizer, set the sterilization parameters to 130℃ for 20 minutes. After sterilization, transfer the spray bottle into the Class A laminar flow workbench through the sealed transfer channel and cool it to room temperature (20-25℃).

[0101] The operator starts the quantitative filling pump in the Class A laminar flow workbench, sets the filling volume to 10ml / bottle, and controls the filling error between 9.9ml and 10.1ml.

[0102] Start the filling equipment and inject the liquid medicine in the sterile storage tank into the spray bottle through the filling pump. During the filling process, keep the air velocity of the Class A laminar flow workbench stable at 0.4-0.5 m / s to avoid airflow fluctuations that may cause contamination.

[0103] For every 50 bottles filled, one bottle is randomly selected and the filling volume is checked using a calibrated volumetric flask to ensure that the accuracy meets the requirements; for every 100 bottles filled, one bottle is randomly selected to test the microbial limit (sterility) of the liquid inside the bottle. If any non-compliance is found, the machine is immediately stopped and the cause is investigated.

[0104] After filling, under Class A laminar flow protection, each spray bottle is immediately capped and sealed with a pump to ensure a tight seal between the bottle and the spray nozzle, with no loosening.

[0105] Example 6

[0106] The difference between this embodiment and Embodiment 1 lies in the testing of seal integrity and spray performance:

[0107] After sealing, the spray bottle is transferred to the vacuum decay test equipment in the Class B clean area. The spray bottle is placed in the test chamber, the vacuum degree is set to -0.07MPa, and it is maintained for 40 seconds. The equipment automatically records the pressure change inside the bottle. The pressure change value is ≤0.005MPa, which is considered qualified. Products with poor sealing that exceed the pressure change value are rejected.

[0108] The sealed and qualified products are transferred to the Class D clean area through the transfer window. 1% of the total product quantity of each batch is sampled (10 bottles are sampled for every 1000 bottles produced in this batch; if less than 20 bottles are produced, 20 bottles are sampled, and an additional 10 bottles are sampled). The sample is fixed on the spray performance testing device, the nozzle is started to spray, and the spray particle size (standard range 10-50μm), spray uniformity (coefficient of variation ≤10%), and content per spray (deviation ≤±5%) are tested. The test data are recorded.

[0109] Comparative Example 1

[0110] The difference between this comparative example and Example 1 is that it does not use the step-by-step feeding sequence of "dissolving excipients first and adding raw materials later", that is:

[0111] During the preparation of the drug solution, under the same conditions, 100.0g of sieved hydroxypropyl-β-cyclodextrin and 5.0g of benzalkonium chloride were added to 8000ml of purified water at 33℃-37℃, along with 50.0ml of glycerol and 50.0g of ribavirin raw material. The mixture was stirred at 300r / min for 45 minutes. During this time, the clarity of the drug solution was observed in real time using an online visual monitoring device built into the stirring tank. If undissolved particles were found in some areas, the stirring time was extended by 5-10 minutes. The remaining 2000ml of purified water was added to adjust the total volume of the drug solution to 10000ml, and the mixture was stirred at the same speed for 5 minutes to ensure that the drug solution was mixed evenly.

[0112] Comparative Example 2

[0113] The difference between this comparative example and Example 1 is that the filtration step uses a conventional two-stage filtration process:

[0114] Open the closed pipeline transport system between the Class C and Class B clean areas and set the pressure inside the pipeline to negative pressure.

[0115] Start the filtration system and first filter the drug solution through a 0.45μm polyethersulfone (PES) filter cartridge at a flow rate of 8 L / h; finally, filter it through a 0.22μm sterile filter cartridge at a flow rate of 6 L / h.

[0116] Comparative Example 3

[0117] The difference between this comparative example and Example 1 is that the aseptic filling process did not use a Class A laminar flow protected environment for filling; instead, it was filled only in a Class B clean area.

[0118] Performance testing

[0119] Product performance tests were conducted on the ribavirin sprays provided in Example 1 and Comparative Examples 1-3.

[0120] Detection methods

[0121] 1. Content uniformity: 10 bottles were randomly selected from each batch of finished product, and the content of the main drug in each bottle was determined by high performance liquid chromatography (HPLC). The average value and relative standard deviation (RSD) were calculated.

[0122] 2. Spray particle size distribution (Dv50): Using a laser diffraction spray particle size analyzer, samples (n=5) of each batch of finished products were taken for measurement, and the median particle size (Dv50) and its distribution range were recorded.

[0123] 3. Content variation per spray: Take the same sample bottle, spray it 10 times consecutively, collect the spray liquid each time, determine its main drug content, and calculate the RSD of the content per spray.

[0124] 4. Dynamic environmental monitoring: During operation, sedimentation discs and airborne bacteria samplers are used to monitor the microorganisms in key areas of the filling point.

[0125] 5. Product sealing test: After filling and sealing, all samples are tested using the vacuum decay method.

[0126] II. Test Results

[0127] As shown in Table 1

[0128] Table 1.

[0129]

[0130] As can be seen from Table 1:

[0131] Comparing Example 1 and Comparative Example 1, the content uniformity of Comparative Example 1 was significantly lower than that of Example 1. The spray droplets were larger and extremely unevenly distributed, with the content difference per spray (RSD=5.8%) far exceeding the acceptable standard. This is mainly because Comparative Example 1 used a simultaneous feeding scheme. Simultaneous feeding resulted in the solubilizer (hydroxypropyl-β-cyclodextrin) not being fully dissolved before contacting the active pharmaceutical ingredient (ribavirin), forming drug encapsulation or localized aggregation. Conventional stirring was insufficient to completely disperse and dissolve it. This not only caused uneven active pharmaceutical ingredient content but also directly led to uneven drug distribution and uncontrolled particle size in the spray droplets.

[0132] Comparing Example 1 and Comparative Example 2, Comparative Example 2 showed a significantly higher airborne bacteria count (8 CFU / m³), a wider spray particle size distribution, and a greater difference in content per spray. This is mainly because Comparative Example 1, using negative pressure transfer, is prone to drawing in unpurified ambient air due to micro-leakage in the pipeline, leading to an increased risk of microbial contamination (deterioration of airborne bacteria data). The lack of a coarse filtration (5 μm) step allows tiny colloidal or insoluble particles in the drug solution to directly enter the fine filtration stage, accelerating the clogging of the fine filter cartridge and potentially causing some particles to penetrate, increasing the risk of large particles remaining in the final drug solution, manifested as a wider spray particle size distribution and decreased uniformity. This demonstrates that the "three-stage filtration (coarse → fine → sterile) + positive pressure closed transfer" system of this invention is an indispensable design for synergistically achieving efficient impurity removal, protecting the final filter cartridge, and maintaining process sterility.

[0133] Comparing Example 1 and Comparative Example 3, the airborne bacterial count in Comparative Example 3 was significantly higher than that in Example 1, and the sealing pass rate was slightly lower. This is because, during open-top filling, without the protection of Grade A unidirectional flow, suspended particles and microorganisms in the Grade B background environment easily settle or enter the product with the airflow, directly leading to an increase in the microbial load at the filling point. Simultaneously, a slightly deteriorated environment may also affect the stability of the sealing operation. This demonstrates that setting up Grade A laminar flow protection in the core filling area is not simply an environmental upgrade, but rather the most critical barrier to minimize the risk of product exposure to microbial contamination and ensure ultimate sterility.

[0134] In summary, this application achieves optimal results in all key quality and safety indicators through "stepwise dissolution, three-stage positive pressure filtration, laminar flow protection filling, and high-sensitivity full-item detection" (Example 1), effectively overcoming the uneven quality and safety risks existing in the prior art.

[0135] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for preparing a ribavirin spray, characterized in that, It includes: (1) In a Class D clean environment, weigh the ribavirin raw material and excipients and sieve them; (2) In a Class C clean environment, the excipients are dissolved in part of purified water, then the ribavirin raw material is added and stirred to dissolve, and purified water is added to the total volume to obtain the drug solution; (3) After the drug solution is passed through a three-stage filtration system of coarse filtration, fine filtration and sterile terminal filtration, it is transferred in a sealed manner to a sterile storage tank in a Class B clean area. (4) Under the conditions of a Class B clean environment and Class A laminar flow protection at the filling site, the medicine liquid in the sterile storage tank is filled into a sterilized spray bottle and sealed immediately; (5) Test the seal integrity and spray performance of the sealed spray bottle.

2. The method for preparing ribavirin spray according to claim 1, characterized in that, In step (1), the excipients include at least a solubilizer, a preservative and a humectant; the ribavirin raw material is sieved through a 100-mesh sieve and the solid components in the excipients are sieved through an 80-mesh sieve.

3. The method for preparing ribavirin spray according to claim 2, characterized in that, Step (2) specifically includes: At a temperature of 33-37℃, the solubilizer, preservative and humectant are first added to purified water at 70%-90% of the prescription amount, and stirred at 250-350 r / min for 10-20 min until completely dissolved; Add ribavirin raw material, keep stirring, and continue to dissolve for 20-40 minutes. During this period, observe the clarity of the solution in real time through an online monitoring system. Add purified water to the full prescription volume, stir and mix well, and then test the pH value and content uniformity of the solution.

4. The method for preparing ribavirin spray according to claim 2, characterized in that, The three-stage filtration system described in step (3) includes: The first stage of filtration is coarse filtration using a 3~7μm pleated filter element; The second stage of filtration is fine filtration using a 0.4~0.5μm filter element; The third stage of filtration is terminal sterilization filtration using a 0.2~0.25μm sterile filter cartridge; During the closed transfer process, the pressure inside the pipeline is maintained at 0.3-0.5 MPa.

5. The method for preparing ribavirin spray according to claim 4, characterized in that, During the three-stage filtration system, the temperature of the drug solution is controlled at 20-25℃ throughout the process. After filtration, the drug solution is tested for microbial limits and visible foreign matter. Only after passing the tests can it be temporarily stored in the sterile storage tank.

6. The method for preparing ribavirin spray according to claim 1, characterized in that, In step (4), the spray bottle is sterilized at 110~130℃ for 20~40min and then cooled in a Class A laminar flow protection environment; the error of the filling amount is controlled within ±1%; during the filling process, the wind speed of the Class A laminar flow protection is 0.36-0.54 m / s.

7. The method for preparing ribavirin spray according to claim 1, characterized in that, In step (5), the seal integrity test adopts the vacuum decay method, which maintains a vacuum condition of -0.07 to -0.09 MPa for 20 to 40 seconds. The pressure change value is ≤0.005 MPa and is considered qualified.

8. The method for preparing ribavirin spray according to claim 1, characterized in that, The spray performance test includes the detection of spray particle size, spray uniformity and content per spray. The spray particle size is controlled within 10~50μm, the coefficient of variation of spray uniformity is ≤10%, and the content deviation per spray is ≤±5%, which is considered as qualified.

9. A ribavirin spray, characterized in that, It is prepared by the preparation method described in any one of claims 1-8.

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