A stable erythromycin ophthalmic ointment composition without preservative and its preparation method

Abstract

The application belongs to the technical field of medicines and the field of ophthalmic preparations, and provides a stable erythromycin ointment composition without preservatives and a preparation method thereof. Through pre-wetting dispersion of erythromycin and liquid paraffin, construction of a white vaseline-liquid paraffin heat-treated oil matrix, low-moisture control, final mixing and redispersion, and nitrogen headspace replacement design, the dispersion state, content uniformity and headspace oxygen level of erythromycin particles are cooperatively controlled, the dispersion stability and chemical stability are improved, the problem that intensive dispersion and stable protection and mild processing and clean production control cannot be considered at the same time is solved, and the stable erythromycin ointment composition without preservatives is suitable for the production of ophthalmic semi-solid preparations without preservatives.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical technology and ophthalmic preparations, specifically to a stable, preservative-free erythromycin eye ointment composition and its preparation method. Background Technology

[0002] Erythromycin eye ointment is a semi-solid ophthalmic preparation, typically used for topical ocular administration. The formulation needs to have appropriate spreadability, retention, and administration comfort within the conjunctival sac, while also ensuring uniform drug dispersion, fine particle size, stable oil matrix, reliable packaging sealing, and aseptic quality control. Publicly available drug labels show that 0.5% erythromycin eye ointment can use erythromycin as the active ingredient and mineral oil and white petrolatum as inactive matrix components, indicating that oil-based matrices remain an important formulation basis for erythromycin eye ointments. For preservative-free eye ointment systems, without relying on common preservatives, the formulation depends more on low moisture control of raw materials, heat treatment of the oil matrix, aseptic filling, and headspace control of packaging to maintain quality stability. Therefore, a suitable process window needs to be established between fine dispersion, chemical stability, aseptic assurance, and production operability.

[0003] Existing erythromycin eye ointment preparation technologies typically focus on the fineness of pulverization, shearing, grinding, and mixing. For example, Chinese patent CN116077420A discloses a process for preparing erythromycin eye ointment, with the background section indicating that the ointment is roughly composed of erythromycin, liquid paraffin, and yellow petrolatum, and focuses on the particulate matter, fineness, and grinding dispersion issues in the ointment. Such approaches help improve particle dispersion and reduce the foreign body sensation during use. However, simply enhancing micronization, shearing, and grinding may increase the exposure interface of the active ingredient, processing thermal history, and quality fluctuations during dispersion. On the other hand, improving chemical stability by increasing oil phase encapsulation, reducing moisture, and enhancing sealing protection may affect the rheology, dispersion uniformity, and final mix operability of the ointment system. Therefore, preservative-free erythromycin eye ointment still requires a holistic approach that considers pre-wetting dispersion, particle size, oil phase coverage, sterile oil matrix, low moisture content, and headspace oxygen control. Summary of the Invention

[0004] The purpose of this invention is to provide a stable, preservative-free erythromycin eye ointment composition and its preparation method, solving the problems of difficulty in simultaneously achieving dispersion stability and chemical stability, and difficulty in coordinating mild processing window and clean production control in current erythromycin eye ointments.

[0005] This invention establishes the wetting and dispersion state of the particulate oil phase by first using an erythromycin-liquid paraffin pre-wetting dispersion, and then introduces it into a low-moisture white petrolatum-liquid paraffin heat-treated oil matrix. Combined with final mixing and redispersion, degassing, clean filling and nitrogen headspace replacement, the particulate dispersion state and oil phase protection conditions are coordinated to achieve both dispersion stability and chemical stability.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A stable, preservative-free erythromycin eye ointment composition, based on a total mass of 100 wt%, comprises the following components and unavoidable impurities:

[0008] Erythromycin, 0.45-0.55 wt%;

[0009] Liquid paraffin, 12.00-20.00 wt%;

[0010] White petroleum jelly, remaining amount;

[0011] The erythromycin was pre-wetted with liquid paraffin and then dispersed in the white petrolatum-liquid paraffin oil matrix;

[0012] In the erythromycin-liquid paraffin pre-wetting dispersion, the mass ratio of erythromycin to liquid paraffin used for pre-wetting is 1:1 to 1:6;

[0013] The erythromycin particles have a D90 of 3.00-15.00 μm;

[0014] The composition is an ophthalmic semi-solid preparation, and the moisture content of the composition is not higher than 0.10 wt%.

[0015] Furthermore, the erythromycin-liquid paraffin pre-wetted dispersion is prepared through the following steps:

[0016] A1. Provides erythromycin micro powder;

[0017] A2. Mix 100 parts by weight of the erythromycin with 100-600 parts by weight of liquid paraffin for pre-wetting, and under nitrogen protection and normal pressure, shear and disperse at 20-40℃ for 5-30 minutes to obtain a pre-wetting slurry;

[0018] A3. The pre-wetted slurry is subjected to three-roll milling for 1-3 passes, and the material temperature is controlled at 20-45℃ during the process;

[0019] A4. When the D90 of erythromycin particles in the pre-wetted slurry is 3.00-15.00 μm, the dispersion process shall be stopped;

[0020] A5. The pre-wetted slurry is defoamed to obtain the erythromycin-liquid paraffin pre-wetted dispersion.

[0021] Furthermore, the white petrolatum-liquid paraffin heat treatment grease matrix is ​​prepared through the following steps:

[0022] B1. Add white petrolatum and liquid paraffin used to prepare the white petrolatum-liquid paraffin heat treatment grease matrix to a melting container at a mass ratio of 4:1-12:1;

[0023] B2. Under nitrogen protection, the mixture is melt-mixed at 70-90℃ for 0.5-2.0h to obtain a homogeneous molten oil matrix;

[0024] B3. After filtering the homogeneous molten oil matrix, heat treatment is carried out at 150-170℃ for 1.0-2.0h;

[0025] B4. Cool to 45-55℃ under nitrogen protection to obtain the white petrolatum-liquid paraffin heat treatment grease matrix;

[0026] B5. The moisture content of the white petrolatum-liquid paraffin heat treatment grease matrix is ​​not higher than 0.05wt%, and it remains in a stirable and fluid state at 45-55℃.

[0027] Furthermore, the composition does not contain benzalkonium chloride, thimerosal, chlorobutanol, benzyl alcohol, phenoxyethanol, methylparaben, or propylparaben; the relative standard deviation of the erythromycin content uniformity in the composition is not higher than 3.00%; after the composition is filled, it is purged with nitrogen and the oxygen volume fraction in the headspace after sealing is not higher than 2.00 vol.

[0028] Furthermore, the D50 of the erythromycin particles is 1.00-6.00 μm.

[0029] As a concept of this invention, the present invention employs a design combining erythromycin-liquid paraffin pre-wetting dispersion with a white petrolatum-liquid paraffin heat-treated oil matrix, primarily to achieve a balance between dispersion stability and chemical stability. In existing technologies, to improve the fineness and uniformity of the ointment, micronization, shearing, or grinding processes are typically enhanced; however, excessive dispersion increases the exposure of erythromycin particles at the interface and raises the risk of processing fluctuations. To improve chemical stability, oil phase wetting is typically enhanced, moisture content reduced, and oxygen contact decreased; however, excessive oil phase protection may increase dispersion resistance and affect final mixing uniformity. This invention first pre-wets erythromycin particles with liquid paraffin before introducing them into a low-moisture oil matrix. By matching the pre-wetting ratio, particle size, and final mixing conditions, particle dispersion and oil phase protection are mutually corrected, thereby obtaining a more stable dispersion state suitable for preservative-free ophthalmic semi-solid formulations. The shearing dispersion, three-roll milling, colloidal dispersion, and low-shear homogenization treatment are used to reduce the agglomeration of erythromycin particles in the oil system and maintain dispersion uniformity, without necessarily reducing the initial particle size of the erythromycin raw material.

[0030] This invention also discloses a method for preparing a stable, preservative-free erythromycin eye ointment composition, comprising the following steps:

[0031] S1. Provide a pre-prepared erythromycin-liquid paraffin pre-wetting dispersion and a pre-prepared white petrolatum-liquid paraffin heat treatment grease matrix, and add the erythromycin-liquid paraffin pre-wetting dispersion into the white petrolatum-liquid paraffin heat treatment grease matrix;

[0032] S2. Stir at 35-50℃ and normal pressure for 10-40 minutes to obtain the final paste;

[0033] S3. The final mixed paste is subjected to three-roll milling for 1-3 passes, and the material temperature is 35-50℃ during the process;

[0034] S4. When the D90 of erythromycin particles in the final mixed paste is 3.00-15.00 μm and the relative standard deviation of the content uniformity is not higher than 3.00%, the final mixing process shall be stopped.

[0035] S5. The final mixed ointment is defoamed, then cleanly filled and sealed to obtain the stable preservative-free erythromycin eye ointment composition.

[0036] Furthermore, when three-roll milling is used in step S3, the gap between the rollers is 5.00-50.00 μm; when both steps S2 and S3 are segmented, the single continuous processing time for each segment is 5-20 min.

[0037] In some embodiments, the final paste can be subjected to low-shear homogenization for 5-30 minutes, during which the material temperature is controlled at 35-50°C, and the D90 of erythromycin particles and the uniformity of content in the final paste are measured after the treatment.

[0038] Furthermore, before filling in step S5, the moisture content of the final mixed paste is not higher than 0.10 wt%.

[0039] Furthermore, after step S3, the D50 of erythromycin particles in the final mixed ointment is 1.00-6.00 μm.

[0040] Furthermore, steps S1 to S5 are all carried out in a clean production environment, and the containers, pipelines, three-roll mill components, homogenizing components and filling components that come into contact with the materials are all sterilized before use.

[0041] Furthermore, before sealing in step S5, headspace is replaced with nitrogen to ensure that the oxygen volume fraction in the headspace after sealing is not higher than 2.00 vol.

[0042] Furthermore, when preparing the stable preservative-free erythromycin eye ointment composition, based on a total mass of 100 parts by mass, the mass of erythromycin is denoted as E, the total mass of liquid paraffin is denoted as L, the mass of liquid paraffin used for pre-wetting is denoted as rE, where r is 1-6, the mass of white petrolatum is 100-LE, the mass of liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix is ​​L-rE, and the mass ratio of white petrolatum to liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix is ​​controlled at 4:1-12:1. The resulting erythromycin-liquid paraffin pre-wetting dispersion and white petrolatum-liquid paraffin heat-treated oil matrix are then introduced into the final ointment preparation step.

[0043] Furthermore, the samples for determining the D50 and D90 of erythromycin particles were derived from corresponding stages of erythromycin micropowder, erythromycin-liquid paraffin pre-wetted dispersion, final mixed paste, or finished paste. During the determination, the samples were diluted with liquid paraffin until the erythromycin particles were in a dispersed state. The cumulative particle size distribution of the erythromycin particles was obtained using microscopic imaging. The particle size corresponding to a cumulative distribution of 50% was taken as D50, and the particle size corresponding to a cumulative distribution of 90% was taken as D90. The D50 and D90 obtained in the same determination stage were used for particle size control determination.

[0044] Furthermore, to characterize the pre-wetting and dispersion state of erythromycin particles in the oil system, the oil phase projection coverage of erythromycin particles was measured. The sample was either an erythromycin-liquid paraffin pre-wetting dispersion or a final mixed paste. During the measurement, the sample was spread into a thin layer with resolvable particle boundaries and no overlap between particles. Images of erythromycin particles were acquired using microscopic image analysis. The projected area of ​​a single erythromycin particle was defined by the projected outline of the particle in the two-dimensional microscopic image, and the continuously covered projected area of ​​the oil phase was defined by the identifiable area within the projected outline that was continuously covered by the oil phase. The ratio of the continuously covered projected area of ​​the oil phase to the projected area of ​​the particle was taken as the single-particle oil phase projection coverage. The arithmetic mean of the single-particle oil phase projection coverage of the tested particles in the same sample was taken as the erythromycin particle oil phase projection coverage. The image acquisition conditions, particle identification rules, and area calculation methods were kept consistent for the same batch of samples. The results were used for recording and quality control of the pre-wetting and dispersion process.

[0045] Furthermore, in the preparation of the erythromycin-liquid paraffin pre-wetted dispersion, the pre-wetted slurry undergoes 1-3 passes of three-roll milling or colloidal dispersion treatment, with the material temperature controlled at 20-45℃ during the treatment. In the embodiment using three-roll milling, the gap between the rollers is 5.00-50.00 μm. The pre-wetted slurry after each treatment pass proceeds to the next treatment pass or degassing step. The treated pre-wetted slurry is used for the determination of erythromycin particle D90 and oil phase projection coverage.

[0046] Furthermore, during the degassing of the pre-wetted slurry, degassing is carried out at 20-40℃, with a degassing pressure of atmospheric pressure or -0.020 to -0.080 MPa and a degassing time of 5-20 min. The degassed material is then used as an erythromycin-liquid paraffin pre-wetted dispersion in the final paste preparation step.

[0047] Further, the homogeneous molten oil matrix is ​​filtered and transferred to a sterilized heat-resistant container. It is then heat-treated at a temperature of 150-170℃ for 1.0-2.0h under nitrogen protection. After heat treatment, the material is cooled to 45-55℃ under nitrogen protection and kept in a stirable and flowable state. The resulting material is used as the white petrolatum-liquid paraffin heat-treated oil matrix in the final paste preparation step.

[0048] Furthermore, the final mixed paste undergoes 1-3 grinding passes during three-roll milling, and the homogenization time during low-shear homogenization is 5-30 minutes. The material temperature is controlled at 35-50℃ during the process. The final mixed paste then proceeds to the steps of determining the D90 content uniformity of erythromycin granules.

[0049] Furthermore, during the degassing of the final mixed paste, degassing is carried out under normal pressure or -0.020 to -0.080 MPa conditions for 5-30 minutes; the degassed final mixed paste then proceeds to the clean filling step.

[0050] Furthermore, when determining the uniformity of erythromycin content, the final mixed paste or finished paste from the pre-filling, mid-filling, and end-filling stages are taken as test samples. The erythromycin content in each sample is obtained using the same erythromycin content determination method. The relative standard deviation of the content uniformity is obtained by dividing the standard deviation of the erythromycin content of each sample by its arithmetic mean and multiplying by 100%. The results are used for the determination of the endpoint of the final mixing process or for the quality control of intra-batch uniformity.

[0051] Furthermore, when determining the oxygen volume fraction in the headspace after sealing, unopened packages that have undergone nitrogen headspace replacement and sealing are used as the test objects. The oxygen volume fraction in the headspace of the package is determined by headspace oxygen analysis, and the measured values ​​are recorded and used for headspace replacement quality control after sealing.

[0052] Furthermore, after clean filling, the stable preservative-free erythromycin eye ointment composition has a single package weight of 0.50-5.00g; after the weight control is completed, the package enters the nitrogen headspace replacement and sealing steps.

[0053] As another aspect of this invention, it employs a step-by-step preparation process involving pre-wetting, heat treatment of the oil-based matrix, low-temperature final mixing and redispersing, degassing, clean filling, and nitrogen headspace displacement. This process is primarily used to achieve, fix, or amplify the aforementioned blending effects. Existing processes, while improving particle dispersion by simply increasing shear and grinding intensity, may also increase active ingredient exposure, heat accumulation, and batch-to-batch fluctuations. Conversely, simply increasing production hygiene control intensity may increase the matrix's thermal history and compress the subsequent final mixing window. This invention limits the high-temperature heat treatment to the white petrolatum-liquid paraffin oil-based matrix stage, allowing erythromycin to undergo pre-wetting and final mixing and dispersion primarily at lower temperatures. Furthermore, degassing and nitrogen headspace displacement after final mixing reduce the risk of residual gas and oxygen contact, thereby coordinating production hygiene control, low moisture control, particle dispersion, and stability protection within the same preparation pathway.

[0054] The erythromycin-liquid paraffin pre-wetting dispersion primarily addresses the initial wetting and dispersion of erythromycin particles in an oil matrix. The white petrolatum-liquid paraffin heat-treated oil matrix primarily addresses the issues of carrying capacity, low moisture content, and production process control in ophthalmic semi-solid formulations. While enhancing erythromycin micronization and grinding dispersion can improve fineness, it can also increase particle surface exposure and weaken chemical stability. Conversely, improving oil phase wetting and matrix protection, while beneficial for reducing the impact of moisture and oxygen contact, may lead to increased dispersion resistance and fluctuations in content uniformity. This invention, through matching the pre-wetting mass ratio, total liquid paraffin content, white petrolatum matrix ratio, final mixing temperature, and redispersion conditions, allows the liquid paraffin to first form a wetted state on the particle surface. Then, the white petrolatum-liquid paraffin heat-treated oil matrix carries and stabilizes this dispersion, ultimately achieving a balance between dispersion stability and chemical stability.

[0055] Beneficial technical effects

[0056] 1. Improve the dispersion state of erythromycin particles: In this invention, erythromycin is first prepared into an erythromycin-liquid paraffin pre-wetting dispersion, and then introduced into a white petrolatum-liquid paraffin heat-treated oil matrix. This ensures that the erythromycin particles have an oil phase wetting foundation before final mixing, which helps to reduce the risk of agglomeration when the dry powder is directly introduced into the oil matrix and improves the content uniformity of the final mixed paste.

[0057] 2. Balancing chemical stability and fine dispersion: This invention limits the D50 and D90 of erythromycin particles and the pre-wetting mass ratio, so that particle dispersion does not solely rely on high-intensity shearing. At the same time, it utilizes liquid paraffin pre-wetting to reduce the degree of direct exposure of particles, thereby forming a more balanced technical path between dispersion stability and chemical stability.

[0058] 3. Enhance the quality control foundation of preservative-free systems: This invention does not add benzalkonium chloride, thimerosal, chlorobutanol, benzyl alcohol, phenoxyethanol, methylparaben, or propylparaben. Instead, it uses synergistic control through heat treatment of the oil matrix, low moisture control, clean filling, and nitrogen headspace replacement, which helps reduce the dependence of preservative-free systems on chemical preservatives.

[0059] 4. Enhanced reproducibility of the preparation process: This invention separates the pre-wetting dispersion, matrix melting heat treatment, final mixing and redispersing, degassing and headspace displacement before sealing into monitorable steps, and sets temperature, time, number of passes, particle size, content uniformity and headspace oxygen index, so that those skilled in the art can repeatedly prepare the target composition according to a clear process window.

[0060] 5. Suitable for industrial scale-up of ophthalmic semi-solid formulations: This invention uses commercially available or pharmaceutical-grade raw materials, conventionally available three-roll milling, colloidal dispersion, low-shear homogenization, defoaming, and clean filling processes, enabling formula calculation, quality testing, and packaging control to be integrated across production batches, which helps improve batch consistency in scale-up production. Attached Figure Description

[0061] Figure 1 The graph shows the effect of the pre-wetting mass ratio on the content uniformity and stability in Example 1.

[0062] Figure 2 The graph shows the effect of the total amount of liquid paraffin on the uniformity and stability of the content in Example 1.

[0063] Figure 3 The graph shows the effect of D90 of erythromycin granules in Example 1 on the uniformity and stability of the content.

[0064] Figure 4 The graph shows the effect of the final mixing temperature (S2) on the uniformity and stability of the content in Example 1.

[0065] Figure 5 The particle size frequency distribution diagrams of erythromycin particles in Example 1, Comparative Example 5, and Comparative Example 9 are shown.

[0066] Figure 6 The cumulative particle size distribution of erythromycin particles in Example 1, Comparative Example 5, and Comparative Example 9 is shown in the diagram.

[0067] Figure 7 This is a summary diagram of the D50 and D90 of erythromycin granules from Examples 1, 5, and 9.

[0068] Figure 8 The image shows a scatter plot of the oil phase projection coverage of erythromycin particles in Examples 1, 3, and 6.

[0069] Figure 9This is a combined record of moisture content and headspace oxygen volume fraction for Example 1, Comparative Example 7, and Comparative Example 8.

[0070] Figure 10 The graph shows the correlation between the content uniformity RSD and the accelerated content retention rate over 30 days for Examples 1, Comparative Examples 9 and 10.

[0071] Figure 11 This is a comparison of macroscopic optical photographs of the final product of Example 1 and the final product of Comparative Example 5; wherein, Figure 11 Figure a in the image is a macroscopic optical photograph of the final product of Example 1; Figure 11 Figure b in the figure is a macroscopic optical photograph of the final product of Comparative Example 5.

[0072] Figure 12 The images show a comparison of the SEM morphology of the final product of Example 1 and the final product of Comparative Example 5; where, Figure 12 Figure a in the image is a low-magnification SEM image of the final product of Example 1; Figure 12 Figure b in the image is a low-magnification SEM image of the final product of Comparative Example 5; Figure 12 Figure c in the image is a medium-magnification SEM image of the final product of Example 1; Figure 12 The d-image in the image is a medium-magnification SEM image of the final product of Comparative Example 5; Figure 12 Figure e in the image is a high-magnification SEM image of the final product of Example 1; Figure 12 Figure f in the image is a high-magnification SEM image of the final product of Comparative Example 5.

[0073] Figure 13 The images shown are macroscopic optical photographs illustrating the evolution of the erythromycin-liquid paraffin pre-wetted dispersion, the white petrolatum-liquid paraffin heat-treated oil matrix, the paste after final mixing with three rollers, and the final product in Example 1. Figure 13 Figure a in the image is a macroscopic optical photograph of the erythromycin-liquid paraffin pre-wetted dispersion; Figure 13 Image b in the image is a macroscopic optical photograph of a white petrolatum-liquid paraffin heat-treated grease matrix; Figure 13 Figure c in the image is a macroscopic optical photograph of the paste after final mixing with three rollers; Figure 13 The d-image in the image is a macroscopic optical photograph of the final product. Detailed Implementation

[0074] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0075] Example 1

[0076] Overall preparation scale and product form: This embodiment prepares 1000.00g of stable, preservative-free erythromycin eye ointment composition, in the form of a semi-solid ophthalmic preparation, with a single package weight of 0.50g. Based on a total composition mass of 100.00wt%, the amount of erythromycin used in this embodiment is 0.45wt%, the total amount of liquid paraffin is 12.00wt%, and the amount of white petrolatum is 87.55wt%.

[0077] Raw materials, components, or material specifications: Erythromycin is commercially available pharmaceutical-grade erythromycin micronized powder with a purity ≥98.0%, moisture content ≤1.0%, and erythromycin particle D90 of 3.00μm. Liquid paraffin is commercially available pharmaceutical-grade liquid paraffin with a moisture content ≤0.02wt%. White petrolatum is commercially available pharmaceutical-grade white petrolatum with a moisture content ≤0.02wt%. Nitrogen gas used in production has a purity ≥99.9%. Melting containers, pipelines, three-roll mill components, degassing components, and filling components that come into contact with the materials are sterilized before use.

[0078] Step 1: Preparation of erythromycin-liquid paraffin pre-wetting dispersion. Weigh 4.50 g of erythromycin and 4.50 g of liquid paraffin for pre-wetting, making the mass ratio of erythromycin to liquid paraffin 1:1. Add the liquid paraffin to a sterilized shear dispersion container and start shear dispersion under nitrogen protection, atmospheric pressure, and 20°C at a speed of 1200 r / min. Then, add erythromycin micronized powder in batches and shear disperse for 5 min to obtain a pre-wetting slurry. Perform a three-roll milling process once, with a roller gap of 5.00 μm and a material temperature controlled at 20°C. After processing, take samples for testing. The D90 of erythromycin particles is 3.00 μm, the D50 of erythromycin particles is 1.00 μm, and the oil phase projection coverage of erythromycin particles is 60.00%. Then, degas for 5 min at 20°C and atmospheric pressure to obtain the erythromycin-liquid paraffin pre-wetting dispersion.

[0079] Step 2: Preparation of the white petrolatum-liquid paraffin heat-treated grease matrix. Weigh 875.50 g of white petrolatum and 115.50 g of liquid paraffin for preparing the white petrolatum-liquid paraffin heat-treated grease matrix, making the mass ratio of white petrolatum to liquid paraffin grease 7.58:1. Add the white petrolatum to the melting container, then add the liquid paraffin. Melt and mix at 70°C for 0.5 h under nitrogen protection, stirring at 80 r / min. Filter the homogeneous molten grease matrix through a sterilized filter and transfer it to a sterilized heat-resistant container. Heat treat at 150°C for 1.0 h under nitrogen protection. After heat treatment, cool to 45°C under nitrogen protection, maintaining a stirable and flowable state. Sampling and testing showed that the moisture content of the white petrolatum-liquid paraffin heat-treated grease matrix was 0.05 wt%.

[0080] Step 3: Preparation of the final paste. The erythromycin-liquid paraffin pre-wetted dispersion obtained in Step 1 was added to the white petrolatum-liquid paraffin heat-treated grease matrix obtained in Step 2. The mixture was stirred for 10 minutes at 35°C, atmospheric pressure, and nitrogen protection, with a stirring speed of 100 r / min, to obtain the final paste. The final paste was then subjected to a three-roll mill for one pass, with a roller gap of 5.00 μm. The material temperature during the process was 35°C, and the single continuous processing time was 5 minutes.

[0081] Step 4: Degassing, Filling, and Sealing. The final paste mixture was tested; the erythromycin particle D90 was 3.00 μm, the erythromycin particle D50 was 1.00 μm, the relative standard deviation of content uniformity was 3.00%, the erythromycin content was 90.00% of the labeled amount, and the moisture content of the final paste mixture was 0.10 wt%. The final paste mixture was degassed for 5 minutes under normal pressure, clean-filled, and then headspace purged with nitrogen. After sealing, the oxygen volume fraction in the headspace was 2.00 vol.

[0082] Quality Inspection Methods and Results: A sample of the finished ointment was taken and diluted with liquid paraffin until the erythromycin particles were dispersed. At least 500 particles were counted using a microscopic imaging method, yielding a D50 of 1.00 μm and a D90 of 3.00 μm for the erythromycin particles. The oil phase projection coverage of the erythromycin particles was determined using microscopic imaging analysis, and the recorded value was 60.00%. Samples from the pre-filling, mid-filling, and post-filling stages were taken to determine the erythromycin content, and the relative standard deviation of the content uniformity was calculated to be 3.00%. The moisture content of the finished product was determined to be 0.10 wt% using a moisture determination method. The oxygen volume fraction in the headspace after sealing was determined to be 2.00 vol% using a headspace oxygen analysis method.

[0083] Features and application scenarios of this embodiment: This embodiment adopts the implementation method of combining the lower limit of the parameter range. The amount of erythromycin, the total amount of liquid paraffin, the pre-wetting ratio, the dispersion temperature and the processing time are all in the lower range, which is suitable for demonstrating the feasibility of ophthalmic semi-solid preparations under conditions of low liquid paraffin dosage and low processing intensity.

[0084] Example 2

[0085] Raw materials and proportions: A stable, preservative-free erythromycin eye ointment composition was prepared at a production scale of 1000.00g, with each package containing 5.00g. 5.50g of commercially available pharmaceutical-grade erythromycin micronized powder was weighed; the erythromycin particle D90 was 15.00μm, the erythromycin particle D50 was 6.00μm, and the purity was ≥98.0%. 200.00g of commercially available pharmaceutical-grade liquid paraffin was weighed, of which 33.00g was used to pre-wet the erythromycin, and 167.00g was used to prepare a white petrolatum-liquid paraffin heat-treated oil matrix. 794.50g of commercially available pharmaceutical-grade white petrolatum was weighed. The nitrogen gas used in production had a purity ≥99.9%. Containers, pipelines, three-roll mill components, and filling components that come into contact with the materials were sterilized before use.

[0086] Preparation process: 33.00 g of pre-wetting liquid paraffin was added to a sterilized shear dispersion container and stirred under nitrogen protection, normal pressure, and 40°C. 5.50 g of erythromycin micropowder was added in batches, and shear dispersion was carried out for 30 min at a shear speed of 1800 r / min to obtain a pre-wetting slurry. The mass ratio of erythromycin to pre-wetting liquid paraffin was 1:6. The pre-wetting slurry was subjected to three-roll milling for three passes with a roller gap of 50.00 μm. Material was collected and re-fed after each pass. The material temperature was controlled at 45°C during the process. Samples were taken after processing and measured. The D90 of erythromycin particles was 15.00 μm, the D50 of erythromycin particles was 6.00 μm, and the oil phase projection coverage of erythromycin particles was 95.00%. Degassing was carried out at 40°C and -0.080 MPa for 20 min to obtain the erythromycin-liquid paraffin pre-wetting dispersion.

[0087] Preparation of the heat-treated oil matrix: 794.50 g of white petrolatum and 167.00 g of liquid paraffin used as the matrix were added to a melting container. The mass ratio of white petrolatum to liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix was 4.76:1. Under nitrogen protection, the mixture was melted and mixed at 90 °C for 2.0 h with a stirring speed of 150 r / min to obtain a homogeneous molten oil matrix. After filtration, the matrix was transferred to a sterilized heat-resistant container and heat-treated at 170 °C for 2.0 h under nitrogen protection. After heat treatment, the matrix was cooled to 55 °C under nitrogen protection and maintained in a stirable and flowable state. The moisture content of the matrix was measured to be 0.03 wt%.

[0088] Post-processing: The erythromycin-liquid paraffin pre-wetted dispersion was added to the white petrolatum-liquid paraffin heat-treated oil matrix and stirred for 40 min at 50°C, atmospheric pressure, and nitrogen protection to obtain the final mixture. The final mixture was then subjected to three-roll milling three times, with a roller gap of 50.00 μm. The material temperature during the process was 50°C. When steps S2 and S3 were performed in stages, the single continuous processing time was 20 min. After the final mixture was completed, it was degassed for 30 min at -0.080 MPa, followed by clean filling, nitrogen headspace purging, and sealing.

[0089] Quality testing methods and results: The final mixed paste and the finished paste were tested for particle size, oil phase projection coverage, content uniformity, moisture content, and headspace oxygen content. In the finished paste, the D50 of erythromycin particles was 6.00 μm, the D90 was 15.00 μm, the oil phase projection coverage of erythromycin particles was 95.00%, the relative standard deviation of content uniformity was 2.10%, the erythromycin content was 110.00% of the labeled amount, the moisture content was 0.08 wt%, and the oxygen volume fraction in the headspace after sealing was 0.50 vol%. At least 500 particles were counted for particle size analysis, and the content uniformity samples were taken from the pre-filling, mid-filling, and post-filling stages.

[0090] The features of this embodiment are: This embodiment adopts an implementation method with the upper limit of the parameter range. The total amount of liquid paraffin, the pre-wetting ratio, the processing temperature, the processing time, and the packaging amount are all in the higher range, which is suitable for the preparation of compositions that exhibit high oil phase wetting and strong final mixing and dispersion conditions.

[0091] Example 3

[0092] In this embodiment, a stable, preservative-free erythromycin eye ointment composition was prepared on a scale of 1000.00g. The composition included 5.00g of erythromycin, 150.00g of liquid paraffin, and 845.00g of white petrolatum. 15.00g of the liquid paraffin was used to pre-wet the erythromycin, and 135.00g was used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix. The erythromycin was commercially available pharmaceutical-grade erythromycin micropowder with a purity ≥98.0% and an initial erythromycin particle D90 of 9.00μm. Both the liquid paraffin and white petrolatum were commercially available pharmaceutical-grade raw materials with a moisture content ≤0.02wt%.

[0093] The erythromycin-liquid paraffin pre-wetting dispersion was prepared using a colloidal dispersion route. 15.00 g of liquid paraffin was added to a sterilized colloidal dispersion container. Under nitrogen protection, atmospheric pressure, and 25°C, 5.00 g of erythromycin micropowder was slowly added, and the mixture was sheared and dispersed for 15 min to obtain a pre-wetting slurry. The mass ratio of erythromycin to liquid paraffin used for pre-wetting was 1:3. The pre-wetting slurry underwent two colloidal dispersion treatments, with the material temperature controlled at 30°C during the treatment. After each treatment, the pre-wetting slurry was collected and fed into the next treatment. After treatment, the erythromycin particle D50 was measured to be 3.50 μm, the erythromycin particle D90 was 9.00 μm, and the oil phase projection coverage of the erythromycin particles was 78.00%. Subsequently, the mixture was degassed for 12 min at 30°C and -0.050 MPa to obtain the erythromycin-liquid paraffin pre-wetting dispersion.

[0094] The white petrolatum-liquid paraffin heat-treated grease matrix was prepared under moderate heat treatment conditions. 845.00 g of white petrolatum and 135.00 g of liquid paraffin (used as the matrix) were added to a melting vessel, with a mass ratio of white petrolatum to liquid paraffin (used for preparing the white petrolatum-liquid paraffin heat-treated grease matrix) of 6.26:1. Under nitrogen protection, the mixture was melt-mixed at 80°C for 1.0 h with a stirring speed of 120 r / min to obtain a homogeneous molten grease matrix. After filtration, the matrix was transferred to a sterilized heat-resistant container and heat-treated at 160°C for 1.5 h, followed by cooling to 50°C under nitrogen protection. The resulting matrix remained in a stirable, flowable state at 50°C, with a moisture content of 0.04 wt%.

[0095] For final mixing, the white petrolatum-liquid paraffin heat-treated oil matrix was first maintained at 42℃, and then the erythromycin-liquid paraffin pre-wetted dispersion was added. The mixture was stirred for 25 minutes under normal pressure at a stirring speed of 130 r / min to obtain the final paste. The final paste was then subjected to low-shear homogenization for 15 minutes, with the material temperature controlled at 42℃. After the treatment, samples were taken; the erythromycin particle D50 was 3.50 μm, the erythromycin particle D90 was 9.00 μm, and the relative standard deviation of content uniformity was 1.50%. The final paste was degassed at -0.050 MPa for 18 minutes, and then filled, purged with nitrogen headspace, sealed, and inspected in a clean production environment. Each package contained 2.50 g.

[0096] Quality testing methods and results: In this embodiment, the finished ointment was analyzed using microscopic imaging, and the D50 of the erythromycin particles was 3.50 μm and the D90 was 9.00 μm. The oil phase projection coverage of the erythromycin particles was 78.00% as determined by microscopic image analysis. The erythromycin content, measured as 100.00% of the labeled amount in samples from the pre-filling, middle-filling, and post-filling stages, had a relative standard deviation of 1.50% for content uniformity. The moisture content was 0.06 wt%, and the headspace oxygen volume fraction was 1.00 vol%. All test items were determined using the corresponding testing methods.

[0097] The applicable scenarios for this embodiment are as follows: This embodiment adopts intermediate ratio, colloidal dispersion and medium final mixing conditions, which is suitable for demonstrating the process adaptability under different dispersion routes, and is suitable for preparing a preservative-free erythromycin eye ointment composition with moderate dosage and high requirements for dispersion uniformity.

[0098] Example 4

[0099] I. Preparation Object and Key Parameters: A 1000.00g stable, preservative-free erythromycin eye ointment composition was used as the preparation object. The composition contained 5.50g of erythromycin, 120.00g of total liquid paraffin, and 874.50g of white petrolatum. 33.00g of liquid paraffin was used for pre-wetting, and 87.00g was used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix. The mass ratio of erythromycin to pre-wetting liquid paraffin was 1:6, and the mass ratio of white petrolatum to the liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated oil matrix was 10.05:1. The single package weight was 1.00g.

[0100] II. Raw Material Conditions and Production Environment: Erythromycin is commercially available pharmaceutical-grade erythromycin micronized powder with a purity ≥98.0%, an initial erythromycin particle D90 of 14.00 μm, and an erythromycin particle D50 of 5.50 μm. Liquid paraffin is commercially available pharmaceutical-grade liquid paraffin with a moisture content ≤0.02wt%. White petrolatum is commercially available pharmaceutical-grade white petrolatum with a moisture content ≤0.02wt%. The production environment is a clean production environment; containers, pipelines, three-roll mill components, homogenizing components, and filling components that come into contact with the materials are all sterilized before use.

[0101] III. Pre-wetting and Dispersion Steps: 33.00 g of liquid paraffin for pre-wetting was added to a shear dispersion container and stirred under nitrogen protection, atmospheric pressure, and 35°C. Then, 5.50 g of erythromycin micropowder was added in batches, and shear dispersion was performed for 20 min at a shear speed of 1600 r / min to obtain a pre-wetted slurry. The pre-wetted slurry was subjected to three-roll milling in three passes with a roller gap of 30.00 μm, and the material temperature was controlled at 40°C during the process. Samples of the pre-wetted slurry after each pass were taken for determination of erythromycin particle D90 and erythromycin particle oil phase projection coverage. After the third pass, the erythromycin particle D90 was 14.00 μm, the erythromycin particle D50 was 5.50 μm, and the erythromycin particle oil phase projection coverage was 90.00%. Subsequently, degassing was performed at 35°C and -0.020 MPa for 20 min to obtain the erythromycin-liquid paraffin pre-wetted dispersion.

[0102] IV. Preparation Steps of Heat-Treated Oil Matrix: 874.50g of white petrolatum and 87.00g of liquid paraffin (used as the matrix) were added to a melting container and melted and mixed at 75℃ for 1.5h under nitrogen protection, with a stirring speed of 100r / min, to obtain a homogeneous molten oil matrix. The homogeneous molten oil matrix was filtered and transferred to a sterilized heat-resistant container, and heat-treated at 170℃ for 1.0h under nitrogen protection. The heat-treated material was cooled to 45℃ under nitrogen protection and kept in a stirable, flowable state at 45℃. Sampling and testing showed that the moisture content of the white petrolatum-liquid paraffin heat-treated oil matrix was 0.04wt%.

[0103] V. Final Mixing, Degassing, and Filling Steps: The erythromycin-liquid paraffin pre-wetted dispersion was added to the white petrolatum-liquid paraffin heat-treated oil matrix and stirred for 20 minutes at 45°C and normal pressure to obtain the final mixture. The final mixture was then subjected to three-roll milling three times, with a roller gap of 30.00 μm. The material temperature during the process was 45°C. When steps S2 and S3 were performed in stages, the single continuous processing time was 10 minutes. After processing, the final mixture was degassed for 30 minutes at -0.020 MPa, followed by clean filling, nitrogen headspace purging, and sealing.

[0104] VI. Quality Testing Methods and Results: The final paste contained erythromycin particles with a D50 of 5.50 μm and a D90 of 14.00 μm. The oil phase projection coverage of the erythromycin particles was 90.00%, the relative standard deviation of content uniformity was 1.80%, and the erythromycin content was 105.00% of the labeled amount. The moisture content of the finished paste was 0.07 wt%, and the oxygen volume fraction in the headspace after sealing was 1.50 vol%. Particle size and oil phase projection coverage were determined using statistical methods based on microscopic images. Content uniformity was determined using samples from the pre-filling, mid-filling, and post-filling stages. Moisture and headspace oxygen were determined using appropriate quality control methods.

[0105] The process features and application directions of this embodiment: This embodiment adopts a high pre-wetting ratio, a high proportion of white petrolatum and medium final mixing conditions, which is suitable for the preparation of preservative-free ophthalmic semi-solid formulations under conditions that reflect high oil phase wetting and high matrix consistency.

[0106] Comparative Example 1: Basically the same as Example 1, except that the amount of erythromycin was 0.40 wt%, the total amount of liquid paraffin was 12.00 wt%, the amount of white petrolatum was 87.60 wt%, the amount of liquid paraffin used for pre-wetting was 4.50 g, and the mass ratio of erythromycin to liquid paraffin used for pre-wetting was 1:1.125; other conditions were kept as follows: preparation scale 1000.00 g, erythromycin micro powder was commercially available pharmaceutical grade, pre-wetting shear temperature 20°C, shearing time 5 min, three-roll milling once, roller gap 5.00 μm, white petrolatum-liquid paraffin heat-treated oil matrix melted at 70°C for 0.5 h and heat-treated at 150°C for 1.0 h, final mixing temperature 35°C, final mixing time 10 min, three-roll milling once after final mixing, final mixed paste degassing at normal pressure for 5 min, clean filling 0.50 g, and sealed after headspace replacement with nitrogen.

[0107] Comparative Example 2: Basically the same as Example 1, except that the total amount of liquid paraffin was 10.00 wt%, the amount of erythromycin was 0.45 wt%, the amount of white petrolatum was 89.55 wt%, the amount of liquid paraffin used for pre-wetting was 4.50 g, and the amount of liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated grease matrix was 95.50 g; other conditions were kept as follows: preparation scale 1000.00 g, erythromycin micro powder was commercially available pharmaceutical grade, the mass ratio of erythromycin to liquid paraffin used for pre-wetting was 1:1, the pre-wetting shear temperature was 20°C, the shearing time was 5 min, three-roll milling was performed once, the gap between the rollers was 5.00 μm, the matrix was melted at 70°C for 0.5 h and heat-treated at 150°C for 1.0 h, the final mixing temperature was 35°C, the final mixing time was 10 min, three-roll milling was performed once after final mixing, the final mixed paste was degassed at normal pressure for 5 min, clean filling was performed at 0.50 g, and the filling was sealed after headspace replacement with nitrogen.

[0108] Comparative Example 3: Basically the same as Example 1, except that the liquid paraffin used for pre-wetting was 2.25g, the mass ratio of erythromycin to liquid paraffin used for pre-wetting was 1:0.5, the total amount of liquid paraffin was still 12.00wt%, and the liquid paraffin used to prepare the white petrolatum-liquid paraffin heat-treated grease matrix was 117.75g; other conditions were kept as follows: preparation scale 1000.00g, erythromycin 4.50g, white petrolatum 875.50g, pre-wetting shear temperature 20℃, shearing time 5min, three-roll milling once, roller gap 5.00μm, matrix melted at 70℃ for 0.5h and heat-treated at 150℃ for 1.0h, final mixing temperature 35℃, final mixing time 10min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5min, clean filling of 0.50g, and sealing after headspace replacement with nitrogen.

[0109] Comparative Example 4: Basically the same as Example 1, except that the pre-wetting shear dispersion was carried out in an air atmosphere; other conditions were kept as follows: preparation scale 1000.00g, erythromycin 4.50g, total liquid paraffin 120.00g, white petrolatum 875.50g, liquid paraffin for pre-wetting 4.50g, the mass ratio of erythromycin to liquid paraffin for pre-wetting was 1:1, shearing temperature 20℃, shearing time 5min, three-roll milling once, roller gap 5.00μm, matrix melted at 70℃ for 0.5h under nitrogen protection and heat-treated at 150℃ for 1.0h, final mixing temperature 35℃, final mixing time 10min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5min, clean filling 0.50g, and sealing after headspace displacement with nitrogen.

[0110] Comparative Example 5: Basically the same as Example 1, except that the D90 of erythromycin particles in the pre-wetting slurry and final mixed paste was controlled to be 18.00 μm; other conditions were maintained as follows: preparation scale 1000.00 g, erythromycin 4.50 g, total liquid paraffin 120.00 g, white petrolatum 875.50 g, liquid paraffin for pre-wetting 4.50 g, mass ratio of erythromycin to liquid paraffin for pre-wetting 1:1, nitrogen protection, shearing temperature 20°C, shearing time 5 min, three-roll milling once, roller gap adjusted to 80.00 μm, matrix melted at 70°C for 0.5 h and heat-treated at 150°C for 1.0 h, final mixing temperature 35°C, final mixing time 10 min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5 min, clean filling 0.50 g, and sealing after headspace replacement with nitrogen.

[0111] Comparative Example 6: Basically the same as Example 1, except that the projection coverage of erythromycin particles in the oil phase was controlled at 45.00%; other conditions were kept as follows: preparation scale 1000.00g, erythromycin 4.50g, total liquid paraffin 120.00g, white petrolatum 875.50g, liquid paraffin for pre-wetting 4.50g, mass ratio of erythromycin to liquid paraffin for pre-wetting 1:1, nitrogen protection, shear temperature 20℃, shear time shortened to 3min, three-roll milling once, roller gap 5.00μm, matrix melted at 70℃ for 0.5h and heat-treated at 150℃ for 1.0h, final mixing temperature 35℃, final mixing time 10min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5min, clean filling 0.50g, and sealing after headspace replacement with nitrogen.

[0112] Comparative Example 7: Basically the same as Example 1, except that the moisture content of the finished paste was controlled at 0.15wt%; other conditions were maintained as follows: preparation scale 1000.00g, erythromycin 4.50g, total liquid paraffin 120.00g, white petrolatum 875.50g, liquid paraffin for pre-wetting 4.50g, the mass ratio of erythromycin to liquid paraffin for pre-wetting was 1:1, nitrogen protection, pre-wetting shear temperature 20℃, shearing time 5min, three-roll milling once, roller gap 5.00μm, matrix melted at 70℃ for 0.5h and heat-treated at 150℃ for 1.0h, final mixing temperature 35℃, final mixing time 10min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5min, clean filling 0.50g, and sealing after headspace replacement with nitrogen.

[0113] Comparative Example 8: Basically the same as Example 1, except that the oxygen volume fraction in the headspace after sealing was 5.00 vol%. Other conditions were maintained as follows: preparation scale 1000.00 g, erythromycin 4.50 g, total liquid paraffin 120.00 g, white petrolatum 875.50 g, liquid paraffin for pre-wetting 4.50 g, erythromycin to liquid paraffin for pre-wetting mass ratio 1:1, nitrogen protection, pre-wetting shear temperature 20°C, shearing time 5 min, three-roll milling once, roller gap 5.00 μm, matrix melted at 70°C for 0.5 h and heat-treated at 150°C for 1.0 h, final mixing temperature 35°C, final mixing time 10 min, three-roll milling once after final mixing, final mixed paste degassing at atmospheric pressure for 5 min, clean filling of 0.50 g, headspace replacement with nitrogen and sealing, so that the oxygen volume fraction in the headspace after sealing was 5.00 vol.

[0114] Comparative Example 9: Basically the same as Example 1, except that instead of preparing a pre-wetting dispersion of erythromycin-liquid paraffin, 4.50g of erythromycin micropowder was directly added to a heat-treated oil matrix of white petrolatum-liquid paraffin, and then the original 4.50g of liquid paraffin used for pre-wetting was added. The total amount of liquid paraffin at the final mixing was still 120.00g. Other conditions were kept as follows: preparation scale 1000.00g, erythromycin 4.50g, white petrolatum 875.50g, white petrolatum-liquid paraffin heat-treated oil matrix melted at 70℃ for 0.5h and heat-treated at 150℃ for 1.0h, final mixing temperature 35℃, final mixing time 10min, three-roll milling once after final mixing, roller gap 5.00μm, degassing of the final mixed paste at normal pressure for 5min, clean filling of 0.50g, and sealing after headspace replacement with nitrogen. This comparative example was used to investigate the compatibility between erythromycin-liquid paraffin pre-wetted dispersion and white petrolatum-liquid paraffin heat-treated oil matrix.

[0115] Comparative Example 10: Basically the same as Example 1, except that the white petrolatum-liquid paraffin oil matrix was not heat-treated at 150°C for 1.0h, and was directly cooled to 45°C under nitrogen protection after filtration; other conditions were kept as follows: preparation scale 1000.00g, erythromycin 4.50g, total liquid paraffin 120.00g, white petrolatum 875.50g, liquid paraffin for pre-wetting 4.50g, mass ratio of erythromycin to liquid paraffin for pre-wetting 1:1, pre-wetting shear temperature 20°C, shearing time 5min, three-roll milling once, roller gap 5.00μm, matrix melting at 70°C for 0.5h, final mixing temperature 35°C, final mixing time 10min, three-roll milling once after final mixing, degassing of the final mixed paste under normal pressure for 5min, clean filling of 0.50g, and sealing after headspace displacement with nitrogen. This comparative example was used to investigate the compatibility between heat treatment and mild final mixing and dispersion of a white petrolatum-liquid paraffin oil matrix.

[0116] Comparative Example 11: Essentially the same as Example 1, except the preparation sequence was adjusted. Erythromycin micronized powder was first added to molten white petrolatum and stirred for 5 minutes, followed by the addition of all liquid paraffin for final mixing, preventing the formation of an independent erythromycin-liquid paraffin pre-wetting dispersion. Other conditions remained the same: preparation scale 1000.00 g, erythromycin 4.50 g, total liquid paraffin 120.00 g, white petrolatum 875.50 g, matrix components melted at 70°C for 0.5 h and heat-treated at 150°C for 1.0 h, subsequent final mixing temperature 35°C, final mixing time 10 min, three-roll milling once after final mixing, roller gap 5.00 μm, final mixed paste degassing at atmospheric pressure for 5 min, clean filling 0.50 g, headspace replacement with nitrogen, and sealing. This comparative example was used to examine the compatibility between the pre-wetting sequence and the oil matrix carrying sequence.

[0117] Characterization and performance testing:

[0118] The D50, D90, and particle size distribution of erythromycin particles from Examples 1-4 and Comparative Examples 1-11 were measured to evaluate the effects of pre-wetting, grinding, or homogenization on particle dispersion. During testing, erythromycin micropowder, pre-wetted dispersion, final mixture, or finished paste was diluted with liquid paraffin to achieve particle dispersion. At least 500 particles were counted using microscopic imaging, and D50 and D90 were calculated.

[0119] The oil phase projection coverage of erythromycin particles was measured to evaluate the effect of liquid paraffin pre-wetting on the oil phase wetting state of the particle surface. A pre-wetting dispersion or final mixture was spread into a thin layer with distinguishable particle boundaries and no overlap between particles. At least 20 images were acquired using microscopic image analysis. The proportion of the projected area of ​​a single particle covered by the continuous oil phase in the two-dimensional microscopic image was calculated to the total projected area of ​​the particle, and the arithmetic mean was taken as the oil phase projection coverage.

[0120] The relative standard deviation of erythromycin content and content uniformity was determined to evaluate the intra-batch consistency of the final blend, redispersion, and filling processes. Final blends or finished pastes from the pre-filling, mid-filling, and post-filling stages were taken and measured using the same erythromycin content determination method. The erythromycin content of each sample was recorded, and the relative standard deviation of content uniformity was calculated by dividing the standard deviation by the arithmetic mean and multiplying by 100%.

[0121] The purpose of determining the moisture content of the finished paste is to evaluate the impact of a low-moisture oil matrix, defoaming, and filling processes on moisture control in preservative-free oil systems. Sealed finished paste samples were taken and their moisture content was measured after exposure to ambient moisture; the moisture content of each sample was recorded. Within the same batch of testing, sample quality, solvent system, endpoint criteria, and blank subtraction methods were kept consistent.

[0122] The purpose of measuring the oxygen volume fraction in the headspace of sealed packaging is to evaluate the quality of nitrogen headspace replacement and sealing. Unopened packages that have undergone nitrogen headspace replacement and sealing are taken, and the headspace oxygen volume fraction is determined using headspace oxygen analysis. The oxygen volume fraction of each package sample is recorded, along with the package weight and the integrity of the seal.

[0123] The purpose of determining short-term accelerated stability was to evaluate the synergistic effect between dispersion stability and chemical stability. Sealed samples from the examples and comparative examples were placed at 40°C for 30 days. The retention rate of erythromycin content, the rate of change of D90, and the uniformity of appearance were measured. Initial content, initial particle size, and headspace oxygen level of the packaging were recorded before testing.

[0124] To verify the synergistic effect of erythromycin particle pre-wetting, particle size control, low-moisture oil matrix, mild final mixing, and low-oxygen encapsulation in this scheme, single-factor investigations were conducted on key formulation and process parameters, and the results were evaluated in conjunction with the macroscopic appearance, microscopic morphology, and key quality indicators of the final product. The results show that this scheme can maintain good dispersion of erythromycin particles in an oil matrix without the addition of preservatives, while establishing a corresponding quality control basis through the control of moisture, oxygen, and heat treatment conditions.

[0125] Figure 1 This figure illustrates the effect of the pre-wetting mass ratio on the content uniformity and stability of the present invention. Based on the basic formulation and preparation process of Example 1, only the mass ratio r of liquid paraffin to erythromycin in the pre-wetting stage is changed, where r is the ratio of the mass of liquid paraffin used for pre-wetting to the mass of erythromycin, with a variable range of 0.5-7.0. Figure 1 It is evident that when r is at a low level, liquid paraffin is insufficient to fully wet the surface of erythromycin particles, leading to localized aggregation between particles and a higher relative standard deviation (RSD) for content uniformity. Under 30-day accelerated conditions, the content retention rate is relatively low. As r increases to a moderate range, a more continuous oil phase wettability is formed on the surface of the erythromycin particles, reducing direct contact between particles, improving the uniformity of paste dispersion, and simultaneously improving the content retention rate. When r continues to increase, the amount of free oil phase in the system increases, which in turn affects the structural stability of the semi-solid matrix, causing the RSD to rise again. This indicates that pre-wetting does not simply require increasing the amount of oil phase to achieve better results; rather, a balance must be struck between particle wetting and matrix structural stability.

[0126] After determining the pre-wetting ratio, the impact of the overall oil phase content on the system quality was further investigated. Figure 2 This diagram illustrates the effect of the total amount of liquid paraffin on the uniformity and stability of the content. Based on the basic formulation of Example 1, only the total amount of liquid paraffin was varied, ranging from 10.0 to 22.0 wt%. The results show that when the total amount of liquid paraffin is low, the migration and redispermation of erythromycin particles in the white petrolatum matrix are insufficient, the oil phase wetting on the particle surface is inadequate, and the content uniformity RSD is high. When the total amount of liquid paraffin is controlled at approximately 14.0-18.0 wt%, the system possesses both suitable rheological properties and particle wetting ability, the RSD decreases, and the 30-day accelerated content retention rate is high. When the total amount of liquid paraffin continues to increase, the matrix consistency decreases, the risk of local oil phase enrichment increases, and both the dispersion state and stability are affected. Figure 1 and Figure 2 The results collectively indicate that the oil phase wetting of erythromycin particles needs to be matched with the matrix structure, and a moderate oil phase ratio helps to improve both dispersion stability and chemical stability.

[0127] Figure 3This figure illustrates the effect of D90 on the content uniformity and stability of erythromycin particles according to the present invention. Based on the basic formulation and mixing process of Example 1, only the particle size distribution of erythromycin particles was varied, with D90 ranging from 2.0 to 18.0 μm. The results show that when D90 is too small, although particle refinement helps reduce the risk of visible coarse particles and sedimentation stratification, the particle specific surface area increases significantly, placing higher demands on oil phase wetting and interface protection, and potentially increasing the risk of erythromycin exposure to residual moisture or oxygen. When D90 is too large, the proportion of coarse particles increases, making it difficult for particles to distribute uniformly in the semi-solid matrix, and increasing the content uniformity RSD. When D90 is controlled within the range of approximately 6.0-12.0 μm, the content uniformity RSD is relatively low under the investigated conditions, and the accelerated content retention rate after 30 days is relatively high. These results indicate that there is a synergistic relationship between erythromycin particle refinement and stability protection; an appropriate particle size range can reduce the problem of uneven dispersion of coarse particles while avoiding the risk of interface exposure caused by excessive refinement.

[0128] Figure 4 This graph illustrates the effect of the final mixing temperature (S2) on the uniformity and stability of the content in this invention. The graph is based on the basic formulation of Example 1, with only the final mixing temperature (S2) varied, ranging from 30.0 to 55.0°C. Figure 4 It is evident that when the final mixing temperature is too low, the white petrolatum-liquid paraffin matrix has insufficient fluidity, making it difficult for the erythromycin pre-wetted dispersion to fully enter the matrix continuous phase, resulting in insufficient particle redispersion. When the final mixing temperature is increased to approximately 38.0-46.0℃, the matrix softening degree is suitable, which can meet the redispersion requirements of erythromycin particles without causing significant heat treatment pressure on erythromycin. Therefore, the content uniformity RSD decreases, and the 30-day accelerated content retention rate increases. When the temperature continues to rise to a higher level, the risk of erythromycin being exposed to heat increases, and the stability index decreases. Figure 4 The results further demonstrate that this scheme achieves a balance between improving dispersion and reducing the risk of thermal degradation through a mild final mixing window.

[0129] The above single-factor results indicate that the formulation and process parameters need to be controlled in combination, focusing on the particle interface state, matrix carrying capacity, and heat treatment intensity. To further verify the influence of particle size control on the dispersion state of the system, a comparative analysis was conducted on the particle size distribution of erythromycin particles in Example 1, Comparative Example 5, and Comparative Example 9. Figure 5 This is a particle size frequency distribution diagram of the erythromycin particles of the present invention. (From...) Figure 5As can be seen, the particle size distribution peaks of Example 1 are relatively concentrated, with D50 of approximately 1.00 μm and D90 of approximately 3.00 μm, indicating that the particles can maintain a narrow micron-level distribution after pre-wetting and three-roll processing. The particle size distribution of Comparative Example 5 clearly shifts towards larger particle sizes, with D90 of approximately 18.00 μm, suggesting a significant increase in the proportion of coarse particles. The particle size distribution of Comparative Example 9 is wider, and it contains certain coarse particle tails, indicating that its particle dispersion is not concentrated enough. These results, from a frequency distribution perspective, show that Example 1 can reduce the formation of coarse particles, providing a foundation for the fineness and uniformity of the paste content.

[0130] Figure 6 This is a cumulative particle size distribution diagram of the erythromycin particles of the present invention. This diagram further illustrates the differences in cumulative particle size distribution between Example 1, Comparative Example 5, and Comparative Example 9. The cumulative distribution curve of Example 1 rises rapidly, indicating a higher proportion of smaller particle sizes and fewer large particle tails; the curve of Comparative Example 5 shifts to the right overall, indicating a significant increase in the proportion of large particles and a prominent trend of particle coarsening; the curve of Comparative Example 9 rises more slowly, suggesting a greater degree of particle size dispersion. Figure 5 The frequency distribution results corroborate each other. Figure 6 This indicates that Example 1 can not only reduce the average particle size level, but also control the tail of coarse particles, thereby reducing the risk of local particle enrichment and uneven dispersion.

[0131] Figure 7 This is a summary graph of the D50 and D90 values ​​of the erythromycin particles of this invention. This graph quantitatively compares the key particle size parameters of Example 1, Comparative Example 5, and Comparative Example 9. Example 1 has a D50 of approximately 1.00 μm and a D90 of approximately 3.00 μm, indicating relatively stable particle size control. Comparative Example 5 shows significantly increased D50 and D90, indicating that insufficient three-roll processing or increased gap between rollers makes it difficult to fully disperse coarse particles. Comparative Example 9 also has a higher D90 than Example 1, indicating that a large proportion of particles still exist in its particle size distribution. Combined with… Figure 5 and Figure 6 It can be seen that concentrated particle size distribution and controlled tail of coarse particles are important prerequisites for obtaining a uniform paste structure and provide a physical basis for subsequent stable storage.

[0132] In addition to particle size control, the degree of oil phase projection coverage of erythromycin particles can reflect the oil phase wetting state of the particles in the microscopic image. Figure 8This is a scatter plot of the oil phase projection coverage of erythromycin particles according to the present invention, comparing the oil phase wetting of particle surfaces in Example 1, Comparative Example 3, and Comparative Example 6. The results show that the oil phase projection coverage of particles in Example 1 is approximately 60.00%, and the dispersion of repeated measurements is small, indicating that the pre-wetting and oil phase dispersion steps can stably form an oil phase wetting state for the particles. The oil phase projection coverage of Comparative Examples 3 and 6 is lower, suggesting insufficient wetting of the particle surface and poor interfacial continuity between the particles and the matrix. These results demonstrate that this method does not solely rely on particle size control to improve dispersibility, but rather reduces direct contact and interfacial exposure between particles through oil phase wetting of the particle surface, thus maintaining good dispersion compatibility of the particles in the oil matrix.

[0133] Figure 9 This is a combined recording graph of moisture content and headspace oxygen volume fraction, comparing key environmental control parameters of Example 1, Comparative Example 7, and Comparative Example 8. The finished product of Example 1 had a moisture content of approximately 0.10 wt% and a headspace oxygen volume fraction of approximately 2.00 vol% after sealing; the moisture content of Comparative Example 7 increased to approximately 0.15 wt%, and the headspace oxygen volume fraction of Comparative Example 8 increased to approximately 5.00 vol%. These results indicate that moisture content and headspace oxygen volume fraction can be used as quality control recording indicators for the storage environment of oil systems. Figure 8 It can be seen that the oil phase wetting state of the particle surface, together with the low moisture and low oxygen encapsulation conditions, constitute the relevant control factors for stability evaluation.

[0134] Figure 10 This is a graph showing the relationship between the content uniformity RSD and the 30-day accelerated content retention rate of the present invention, comparing the uniformity and stability of Example 1, Comparative Example 9, and Comparative Example 10. The content uniformity RSD of Example 1 is approximately 3.00%, and the 30-day accelerated content retention rate is approximately 94.0%. The RSDs of Comparative Examples 9 and 10 both increased, while the 30-day accelerated content retention rates decreased. Figure 10 The results show that, in the samples examined, the content uniformity and the 30-day accelerated content retention rate exhibit the same trend.

[0135] To further verify the actual effect of the above parameter control from an intuitive visual perspective, macroscopic optical observation was conducted on the final product. Figure 11 This is a comparison of macroscopic optical photographs of the final product of Example 1 and the final product of Comparative Example 5. Figure 11 Image a is a macroscopic optical photograph of the final product of Example 1. The sample is a 0.50g single-package preservative-free erythromycin eye ointment composition. The erythromycin particles have a D50 of 1.00μm and a D90 of 3.00μm, with an oil phase projection coverage of 60.00%. Figure 11As can be seen, Example 1 was able to form a uniform, continuous and fine semi-solid paste even with a low amount of liquid paraffin and mild processing conditions. Figure 11 b is a macroscopic optical photograph of the final product of Comparative Example 5. The sample is also a preservative-free erythromycin eye ointment composition with a single package weight of 0.50g, but the D90 of the erythromycin particles is controlled to be 18.00μm. Compared with Example 1, Comparative Example 5 shows a decreasing trend in macroscopic uniformity and fineness of the ointment due to the increased gap between the three-roll mill rollers, resulting in coarser particles. Figure 11 The comparison results show that the pre-wetting dispersion, three-roll milling, final mixing and redispersing, and degassing and encapsulation processes can demonstrate good macroscopic uniformity in the final product.

[0136] Based on macroscopic observation, the microscopic distribution of erythromycin particles in the oil matrix was further evaluated by SEM morphology analysis. Figure 12 The image shows a comparison of the SEM morphology of the final product of Example 1 and the final product of Comparative Example 5. Figure 12 a is a low-magnification SEM image of the final product of Example 1, showing that the erythromycin particles are widely dispersed in the white petrolatum-liquid paraffin oil matrix, with no obvious coarse agglomerates, indicating that the particle size control results of D50 of 1.00 μm and D90 of 3.00 μm are consistent with the microstructure. Figure 12 b is a low-magnification SEM image of the final product of Comparative Example 5, which shows coarse erythromycin particles or local particle-rich areas with a D90 of 18.00 μm, indicating that the particle size increased significantly after the roller gap was adjusted to 80.00 μm. Figure 12 c is a magnified SEM image of the final product of Example 1, which further shows that micron-sized erythromycin particles can be distributed in a continuous oil matrix; Figure 12 Image d is a magnified SEM image of the final product of Comparative Example 5, showing larger erythromycin particles and their localized concentrated distribution, suggesting that the coarse-particle-size system is not conducive to the formation of a uniform microstructure. Figure 12 e is a high-magnification SEM image of the final product of Example 1, which shows the interface morphology between the edge of the erythromycin particles and the oil matrix. Figure 12 f is a high-magnification SEM image of the final product of Comparative Example 5, showing the local edges of coarse particles and the heterogeneity of the particle-matrix interface. Figure 12 The SEM morphology images are used to compare the morphology, distribution, and interface morphology of particles in the oil matrix, and are not used as the sole basis for determining the oil phase projection coverage or chemical stability.

[0137] To illustrate the connection between the various process steps in Example 1, the macroscopic state of the pre-wetted dispersion, the heat-treated oil matrix, the paste after final mixing with three rollers, and the final product was continuously observed. Figure 13 This is a diagram showing the evolution of macroscopic optical photographs at each stage in Example 1. Figure 13Image a shows a macroscopic optical photograph of the erythromycin-liquid paraffin pre-wetted dispersion. This sample was obtained by mixing 4.50 g of erythromycin and 4.50 g of liquid paraffin at a 1:1 mass ratio, and then shearing at 1200 r / min for 5 min under nitrogen protection at 20 °C, followed by three-roll processing with a 5.00 μm gap between the rollers. The resulting erythromycin particles had a D50 of 1.00 μm and a D90 of 3.00 μm, with an oil phase projection coverage of 60.00%, indicating that the pre-wetting step can form a fine-particle-size dispersion with sufficient oil phase wetting before final mixing. Figure 13 b is a macroscopic optical photograph of a heat-treated oil matrix of white petrolatum and liquid paraffin. The sample was obtained by melting 875.50g of white petrolatum and 115.50g of liquid paraffin at 70℃ for 0.5h, filtering, and holding at 150℃ under nitrogen for 1.0h. The moisture content was 0.05wt%, indicating that the low-moisture oil matrix can provide a uniform and stable supporting environment for the subsequent dispersion of erythromycin. Figure 13 c is a macroscopic optical photograph of the paste after final mixing with three rollers. This sample is made from... Figure 13 Add the pre-wetting dispersion shown in a Figure 13 After the oil matrix shown in b is stirred at 100 r / min for 10 min under nitrogen protection at 35℃, and then processed by a three-roller with a 5.00 μm gap, the erythromycin particles still maintain a D50 of 1.00 μm and a D90 of 3.00 μm, indicating that the final mixing and secondary three-roller processing did not cause particle coarsening and can maintain the pre-wetting and dispersion state of the previous process. Figure 13 Image d is a macroscopic optical photograph of the final product. The sample was obtained by degassing under normal pressure for 5 minutes, filling with 0.50 g of clean material, purging with nitrogen headspace, and sealing. The moisture content of the finished product was 0.10 wt%, and the headspace oxygen volume fraction after sealing was 2.00 vol%. This indicates that the final product can form a uniform semi-solid state under conditions of low moisture, low oxygen, and stable particle size.

[0138] In conclusion, Figures 1 to 4 The formulation ratio, particle size range, and final mixing temperature demonstrate that the key parameters of this scheme have a suitable window. Figures 5 to 7 From the perspective of particle size distribution, Example 1 demonstrates that it can control coarse particles and particle size dispersion. Figure 8 and Figure 9 The relevant quality control conditions are explained from the aspects of particulate oil phase wetting state and low moisture and low oxygen environment, respectively. Figure 10 This further reflects the changing trend between content uniformity and accelerated content retention rate; Figures 11 to 13The results demonstrate the smooth integration of each step from the perspectives of the final product's appearance, microstructure, and process evolution. These results indicate that this scheme, through a continuous process of "pre-wetting dispersion—low-moisture oil matrix support—mild final mixing and redispersion—defoaming and filling—nitrogen headspace replacement," achieves a synergistic effect between particle dispersion, oil phase wetting, low moisture content, and low oxygen control. This alleviates the difficulties in simultaneously achieving dispersion and chemical stability, and between a mild processing window and hygienic production control, in erythromycin eye ointment.

[0139] Table 1 Performance of Examples and Comparative Examples

[0140]

[0141] The values ​​in Table 1 are the test results recorded for the corresponding samples according to the aforementioned test methods.

[0142] As can be seen from the performance of the examples and comparative examples in Table 1, Examples 1-4 show a relatively balanced trend in terms of D90, oil phase projection coverage, content uniformity, moisture, headspace oxygen, and 30-day accelerated content retention. In the conventional comparative examples, when the pre-wetting ratio is insufficient, D90 is too high, oil phase projection coverage is insufficient, moisture is too high, or headspace oxygen is increased, the relevant dispersion and stability indicators show adverse changes. In the comparative examples of the coordination relationship, after canceling the pre-wetting dispersion, canceling the matrix heat treatment, or changing the pre-wetting sequence, the content uniformity and accelerated content retention both show a downward trend, indicating that there is a mutual coordination relationship between pre-wetting oil phase wetting, heat-treated oil matrix bearing, and low-oxygen sealing.

[0143] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A stable, preservative-free erythromycin eye ointment composition, characterized in that, Based on a total mass of 100 wt%, the composition comprises the following components and unavoidable impurities: Erythromycin, 0.45-0.55 wt%; Liquid paraffin, 12.00-20.00 wt%; White petroleum jelly, remaining amount; The erythromycin was pre-wetted with liquid paraffin and then dispersed in the white petrolatum-liquid paraffin oil matrix; In the erythromycin-liquid paraffin pre-wetting dispersion, the mass ratio of erythromycin to liquid paraffin used for pre-wetting is 1:1 to 1:6; The erythromycin particles have a D90 of 3.00-15.00 μm; The composition is an ophthalmic semi-solid preparation, and the moisture content of the composition is not higher than 0.10 wt%.

2. The stable, preservative-free erythromycin eye ointment composition according to claim 1, characterized in that, The erythromycin-liquid paraffin pre-wetted dispersion was prepared by the following steps: A1. Provides erythromycin micro powder; A2. Mix 100 parts by weight of the erythromycin with 100-600 parts by weight of liquid paraffin for pre-wetting, and under nitrogen protection and normal pressure, shear and disperse at 20-40℃ for 5-30 minutes to obtain a pre-wetting slurry; A3. The pre-wetted slurry is subjected to three-roll milling for 1-3 passes, and the material temperature is controlled at 20-45℃ during the process; A4. When the D90 of erythromycin particles in the pre-wetted slurry is 3.00-15.00 μm, the dispersion process shall be stopped; A5. The pre-wetted slurry is defoamed to obtain the erythromycin-liquid paraffin pre-wetted dispersion.

3. The stable, preservative-free erythromycin eye ointment composition according to claim 1, characterized in that, The white petrolatum-liquid paraffin heat treatment grease matrix is ​​prepared through the following steps: B1. Add white petrolatum and liquid paraffin used to prepare the white petrolatum-liquid paraffin heat treatment grease matrix to a melting container at a mass ratio of 4:1-12:1; B2. Under nitrogen protection, the mixture is melt-mixed at 70-90℃ for 0.5-2.0h to obtain a homogeneous molten oil matrix; B3. After filtering the homogeneous molten oil matrix, heat treatment is carried out at 150-170℃ for 1.0-2.0h; B4. Cool to 45-55℃ under nitrogen protection to obtain the white petrolatum-liquid paraffin heat treatment grease matrix; B5. The moisture content of the white petrolatum-liquid paraffin heat treatment grease matrix is ​​not higher than 0.05wt%, and it remains in a stirable and fluid state at 45-55℃.

4. The stable, preservative-free erythromycin eye ointment composition according to claim 1, characterized in that, The composition does not contain benzalkonium chloride, thimerosal, chlorobutanol, benzyl alcohol, phenoxyethanol, methylparaben, or propylparaben; the relative standard deviation of the erythromycin content uniformity in the composition is not higher than 3.00%; after the composition is filled, it is headspace purged with nitrogen, and the oxygen volume fraction in the headspace after sealing is not higher than 2.00 vol.

5. The stable, preservative-free erythromycin eye ointment composition according to claim 1, characterized in that, The erythromycin particles have a D50 of 1.00-6.00 μm.

6. A method for preparing a stable, preservative-free erythromycin eye ointment composition according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Provide a pre-prepared erythromycin-liquid paraffin pre-wetting dispersion and a pre-prepared white petrolatum-liquid paraffin heat treatment grease matrix, and add the erythromycin-liquid paraffin pre-wetting dispersion into the white petrolatum-liquid paraffin heat treatment grease matrix; S2. Stir at 35-50℃ and normal pressure for 10-40 minutes to obtain the final mixture. S3. The final mixed paste is subjected to three-roll milling for 1-3 passes, and the material temperature is 35-50℃ during the process; S4. When the D90 of erythromycin particles in the final mixed paste is 3.00-15.00 μm and the relative standard deviation of the content uniformity is not higher than 3.00%, the final mixing process shall be stopped. S5. The final mixed ointment is defoamed, then cleanly filled and sealed to obtain the stable preservative-free erythromycin eye ointment composition.

7. The preparation method according to claim 6, characterized in that, When three-roll milling is used in step S3, the gap between the rollers is 5.00-50.00 μm; when both steps S2 and S3 are segmented, the single continuous processing time for each segment is 5-20 min.

8. The preparation method according to claim 6, characterized in that, Before filling in step S5, the moisture content of the final mixed paste shall not exceed 0.10 wt%.

9. The preparation method according to claim 6, characterized in that, Steps S1 to S5 are all carried out in a clean production environment, and the containers, pipelines, three-roll mill components, homogenizing components and filling components that come into contact with the materials are all sterilized before use.

10. The preparation method according to claim 6, characterized in that, Before sealing in step S5, headspace is replaced with nitrogen to ensure that the oxygen volume fraction in the headspace after sealing is no higher than 2.00 vol.

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