A ribitol vitamin B12 oral solution and a method for preparing the same

Abstract

The present application provides a kind of L-lysine inositol vitamin B12 oral solution and its preparation method.The oral solution includes hydrochloric acid lysine, vitamin B12, inositol, sodium benzoate, citric acid, lemon essence, sucrose and caramel color, etc., and pH is controlled at 4.0-4.5.The preparation method of the present application adopts 200 mesh circulating filtration, main drug step feeding, vitamin B12 low-temperature separate dissolution and addition, and can be combined with vacuum degassing, light-proof nitrogen filling, metal ion chelation and 0.45 μm terminal filtration, etc..The method significantly improves the stability of vitamin B12 and lysine in preparation, reduces the dosage of sodium benzoate, improves the clarity and insoluble particle level, and the process is simple and controllable, suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and more specifically, to a lysine inositol vitamin B12 oral solution and its preparation method. Background Technology

[0002] Lysine Inosite and Vitamin B12 Oral Solution is a compound preparation approved for marketing in my country. It was upgraded from a local standard to a national standard product and belongs to the category of Class B over-the-counter (OTC) vitamin drugs. This product consists of three active ingredients: lysine hydrochloride, vitamin B12, and inositol. It is mainly used for loss of appetite and poor growth and development in children caused by lysine deficiency.

[0003] In existing technologies, the formulations of lysine inositol vitamin B12 oral solutions produced by multiple companies are highly similar. A typical formulation (per 1000 mL) is: 60 g lysine hydrochloride, 3 mg vitamin B12, 10 g inositol, 5 g sodium benzoate, 1.5 g citric acid, 6 g lemon flavoring, 450 g sucrose, 0.5 g caramel color, and purified water added to 1000 mL. The preparation process is typically as follows:

[0004] The purified water is heated to boiling, and sucrose, caramel color and sodium benzoate are added in sequence to dissolve. After cooling to about 60°C, lysine hydrochloride, inositol, citric acid and vitamin B12 are added to the mixing tank. The pH is not measured. Water is added directly to the required amount and stirred for about 1 hour. There is no filtration step. Then it is filled and sealed.

[0005] The existing process described above has the following problems:

[0006] 1. Uncontrolled pH and poor drug stability: The solubility of lysine hydrochloride is significantly affected by pH, and it easily crystallizes and precipitates under neutral or slightly alkaline conditions. Similarly, the stability of vitamin B12 in solution is closely related to pH, with literature reporting its optimal stable pH range of approximately 4.0–6.5. Current processes do not detect or adjust pH, leading to increased risks of lysine precipitation and vitamin B12 degradation, resulting in poor batch-to-batch stability.

[0007] 2. High temperature and prolonged exposure accelerate vitamin B12 degradation: Vitamin B12 is highly sensitive to light and temperature. In current processes, vitamin B12 is added to high-concentration syrup at approximately 60°C and coexists with other components for extended periods, making it prone to degradation and resulting in a significant decrease in content within the shelf life.

[0008] 3. High dosage of preservative and poor preservation environment: The dosage of sodium benzoate in the existing prescription is 5 g / 1000 mL, and the pH is not controlled. When the pH of the solution is too high, the ratio of undissociated molecules of benzoic acid / sodium benzoate decreases, and the preservative efficacy decreases. At the same time, the high dosage of sodium benzoate poses a potential safety risk to children's long-term use.

[0009] 4. Lack of fine filtration process, high risk of clarification and insoluble particles: Insoluble particles are easily introduced during the preparation and mixing of syrup. If the syrup is filled directly without a filtration process, it may result in substandard clarification and excessive insoluble particles.

[0010] 5. The effects of oxygen and light are not systematically controlled: The existing process does not consider the effects of dissolved oxygen and oxygen in the headspace on the stability of vitamin B12 and other components, nor does it adopt measures such as light protection or nitrogen purging, which further aggravates the degradation of active ingredients.

[0011] In summary, the existing lysine inositol vitamin B12 oral solution has significant shortcomings in terms of stability, safety, and clarity, and there is an urgent need for systematic optimization in terms of formulation and process. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the purpose of this invention is to significantly improve the chemical stability, microbial preservative efficacy, safety, and clarity of lysine inositol vitamin B12 oral solution by precisely controlling pH, optimizing the order and temperature of adding the main drug, combining vacuum degassing and light-proof nitrogen filling, controlling metal ions, and employing two-stage filtration, based on three established active ingredients and basic dosages. This is achieved through processes such as precise pH control, optimization of the order and temperature of adding the main drug, combined vacuum degassing and light-proof nitrogen filling, control of metal ions, and the use of two-stage filtration. It also enhances the controllability and industrial adaptability of the preparation process.

[0013] To achieve the above objectives, the present invention provides the following technical solution:

[0014] The preferred formulation of the lysine inositol vitamin B12 oral solution of the present invention per 1000 mL is as follows: lysine hydrochloride: 60 g, vitamin B12: 3 mg, inositol: 10 g, sodium benzoate: 4 g, citric acid: 2 g, lemon flavor: 7 g, sucrose: 500 g, caramel color: 0.5 g, and purified water: to 1000 mL.

[0015] Furthermore, the pH of the oral solution was controlled within the range of 4.0 to 4.5.

[0016] This invention provides a method for preparing a lysine inositol vitamin B12 oral solution, comprising:

[0017] (1) Syrup preparation: Add purified water to the mixing tank, heat to boiling, add sucrose and caramel color, continue boiling to sterilize, and obtain syrup solution.

[0018] (2) 200-mesh circulating filtration and cooling: The syrup is filtered through a 200-mesh stainless steel screen at least twice to remove insoluble particles and cooled to below 40°C.

[0019] (3) Adding the main drug and adjusting pH: Dissolve the prescribed amount of lysine hydrochloride, inositol and citric acid in about 10 L of purified water and add it to the syrup obtained in step (2). Stir and mix, and test the pH. Adjust the amount of citric acid to control the pH of the solution at 4.0 to 4.5.

[0020] (4) Dissolve vitamin B12 separately and add it at low temperature: Dissolve vitamin B12 separately in about 1 L of purified water, and add it to the solution obtained in step (3) when the liquid temperature in the mixing tank does not exceed 40 ℃, preferably 35~38 ℃, and stir to mix.

[0021] (5) Add fragrance and water: Dilute lemon fragrance in 95% ethanol and add it to the solution obtained in step (4). Add purified water that has been boiled and cooled to 30-40°C to the target volume. Start stirring and circulation pump to mix for 40 min, then fill and seal.

[0022] Furthermore, the present invention includes a vacuum degassing and light-shielding nitrogen stabilization method:

[0023] Among the above basic methods, the preferred method is:

[0024] After filtration, the syrup is degassed under vacuum at a pressure of -0.06 to -0.09 MPa for 10 to 20 minutes to reduce dissolved oxygen content.

[0025] The steps of adding the main drug, adjusting the pH, adding vitamin B12 and flavoring are carried out under light-protected conditions (light intensity not exceeding 1000 lux), and the mixing tank and infusion pipeline are made of opaque materials;

[0026] Before filling, purge the space inside the bottle with sterile nitrogen for 1–3 seconds, and after sealing, control the headspace oxygen volume fraction to be no higher than 2%.

[0027] Furthermore, the present invention includes a method for controlling and chelating metal ions for stabilization:

[0028] Disodium ethylenediaminetetraacetate (EDTA-2Na) at 0.02–0.10 g / 1000 mL is added during the syrup stage to complex trace metal ions in the solution. Simultaneously, purified water treated by reverse osmosis and EDI is preferred, with a total metal ion content not exceeding 10 μg / L. Furthermore, the inner surfaces of the mixing tank and pipelines are electropolished and passivated to reduce metal precipitation.

[0029] Furthermore, the present invention includes a continuous method for segmented dissolution and online mixing:

[0030] To prepare a highly concentrated mother liquor (e.g., 10x concentrated) of lysine hydrochloride, inositol, and citric acid, the 3-10x concentrated mother liquor of lysine hydrochloride, inositol, and citric acid is mixed online with the main syrup liquor in a continuous or semi-continuous production line using a mass flow meter at a volume ratio of (7-10):1. Then, vitamin B12 solution and diluted flavor ethanol solution are added online downstream of the main liquor, and purified water is added to the target volume to achieve continuous preparation and reduce local supersaturation and high temperature exposure.

[0031] Furthermore, the present invention includes a two-stage filtration and particulate control method:

[0032] Based on the circulating filtration through a 200-mesh sieve, the well-mixed drug solution is then subjected to final filtration through a 0.45 μm microporous membrane at a filtration pressure of 0.1–0.3 MPa to significantly reduce the content of insoluble particles, improve clarity, and stably meet the relevant requirements for oral liquid preparations in the Chinese Pharmacopoeia.

[0033] Furthermore, the present invention includes a method for controlling the amount of flavoring and ethanol used:

[0034] The preferred mass ratio of lemon flavoring to 95% ethanol is 1:(1000-1500), and the mass fraction of ethanol in the final formulation is controlled between 0.5% and 1.0%, taking into account both flavor solubility and drug safety.

[0035] The present invention also provides a lysine inositol vitamin B12 oral solution prepared by any of the above methods, having: a specified formulation and pH 4.0-4.5; a vitamin B12 content retention rate of not less than 90% of the initial labeled amount after 6 months of accelerated storage at 40 °C and 75% relative humidity; and a number of insoluble particles lower than the pharmacopoeia limit after terminal filtration through a 0.45 μm microporous membrane.

[0036] By adopting the above technical solution, the beneficial effects of the present invention are as follows:

[0037] The pharmaceutical chemical stability was significantly improved: by precisely controlling the solution pH to 4.0–4.5, and by dissolving vitamin B12 separately and adding it at a low temperature of 35–38 °C, the degradation and precipitation of vitamin B12 and lysine were significantly slowed down. Accelerated stability experiments showed that the vitamin B12 content retention rate was ≥85% under accelerated conditions for 6 months, preferably ≥90%, which was significantly better than the product prepared by the process of Comparative Example 1.

[0038] Dual control of oxygen and light further reduces the risk of degradation: vacuum degassing and nitrogen sealing effectively reduce dissolved oxygen and headspace oxygen, while the light-shielding process chain reduces photo-induced degradation. The synergistic effect of these three factors further improves the stability of vitamin B12 and lysine.

[0039] Metal ion control enhances long-term stability: By using metal ion chelating agents (such as EDTA-2Na) and controlling metal precipitation in water and equipment, the catalytic effect of metal ions on the degradation of vitamin B12 is weakened.

[0040] Dual-stage filtration and terminal membrane filtration significantly improve clarity and reduce insoluble particles: 200-mesh circulating filtration combined with 0.45μm microporous membrane terminal filtration effectively removes insoluble particles, making the preparation clear and transparent to the naked eye, and the number of insoluble particles is significantly lower than the pharmacopoeia limit, thus improving medication safety.

[0041] Reduced dosage of preservatives without reduced efficacy, improving safety for children: Within the optimal antibacterial range of pH 4.0–4.5, the dosage of sodium benzoate has been reduced from the traditional 5 g / 1000 mL to 4 g / 1000 mL. Combined with process optimization, it still meets the pharmacopoeia requirements for preservative efficacy, achieving "reduced dosage without reduced efficacy" and reducing the potential risks of long-term medication.

[0042] Enhanced process controllability and industrial adaptability: By precisely controlling temperature, pH and mixing time, and introducing unit operations such as vacuum degassing, online mixing and terminal filtration, the process parameters of this invention are clear and reproducible, making it easy to achieve large-scale and standardized production on existing pharmaceutical equipment. Attached Figure Description

[0043] Figure 1 This is an HPLC chromatogram for the determination of vitamin B12 content in lysine inositol vitamin B12 oral solution (sample B, prepared in Example 1) in Example 5 of the present invention. Detailed Implementation

[0044] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0045] Example 1: Basic Preparation Method

[0046] The formulation of the lysine inositol vitamin B12 oral solution of the present invention per 1000 mL is as follows: lysine hydrochloride: 60 g, vitamin B12: 3 mg, inositol: 10 g, sodium benzoate: 4 g, citric acid: 2 g, lemon flavor: 7 g, sucrose: 500 g, caramel color: 0.5 g, purified water: to 1000 mL.

[0047] Preparation steps:

[0048] 1) Preparation of purified water

[0049] Take the amount of purified water specified in the process, heat it to boiling, close the steam valve, and introduce cooling water into the jacket to cool the purified water to below 40 ℃ for later use.

[0050] 2) Syrup preparation

[0051] Add an appropriate amount of purified water to the mixing tank, heat to boiling, add the prescribed amount of sucrose and caramel coloring, maintain boiling for 5 minutes for sterilization, stir to completely dissolve, and obtain syrup.

[0052] 3) 200-mesh circulating filter and cooling

[0053] The syrup solution was circulated and filtered at least twice through a filter equipped with a 200-mesh stainless steel screen to remove insoluble particles. After filtration, cooling water was introduced into the jacket to cool the syrup solution to below 40°C.

[0054] 4) Add the main drug and adjust the pH.

[0055] Dissolve the prescribed amounts of lysine hydrochloride, inositol, and citric acid in approximately 10 L of purified water. Add the resulting solution to a mixing tank and stir thoroughly. Measure the pH and adjust it by adding citric acid to maintain the solution pH between 4.0 and 4.5.

[0056] 5) Dissolve vitamin B12 separately and add it at low temperature.

[0057] Take the prescribed amount of vitamin B12 and dissolve it in about 1 L of purified water. When the liquid temperature in the mixing tank is 35-38 °C, slowly add the vitamin B12 solution to the mixing tank while stirring.

[0058] 6) Add fragrance and mix with water.

[0059] Dilute the lemon flavoring with 95% ethanol (flavoring to ethanol mass ratio 1:1200), mix thoroughly, and then add to the mixing tank. Next, add purified water that has been boiled and cooled to 30–40 °C to bring the total volume to 1000 mL, achieving the required total volume. Turn on the stirrer and circulation pump and mix for 40 minutes to ensure uniform dispersion of all components.

[0060] 7) Filling and sealing

[0061] The liquid medicine is transferred into a filling machine and filled into brown or transparent glass bottles under normal lighting conditions. The bottles are then capped and sealed, and the bottles are inspected under light, labeled, boxed, and packed.

[0062] Example 2: Preparation method involving vacuum degassing and light-proof nitrogen purging

[0063] The formula is the same as in Example 1.

[0064] Preparation steps:

[0065] 1) Syrup preparation and filtration

[0066] Prepare and filter the syrup according to steps 2) and 3) of Example 1.

[0067] 2) Vacuum degassing

[0068] Transfer the filtered syrup into a mixing tank equipped with a vacuum port, start the vacuum pump, adjust the vacuum level inside the tank to -0.08 MPa, and maintain it for 15 minutes to remove dissolved oxygen and air bubbles. After degassing, slowly restore the pressure to normal.

[0069] 3) Cooling and light protection operation

[0070] Cooling water was introduced into the jacket to cool the syrup to about 36 ℃. The entire process was carried out in a light-protected environment with a light intensity of <1000 lux.

[0071] 4) Add the main drug and adjust the pH.

[0072] Add lysine hydrochloride, inositol, and citric acid solution according to step 4 of Example 1, and adjust the pH to 4.0-4.5.

[0073] 5) Dissolve vitamin B12 separately and add it at a low temperature and away from light.

[0074] Dissolve vitamin B12 according to step 5 of Example 1. The dissolution and addition process is carried out under light-protected conditions, and the liquid temperature in the mixing tank is controlled at 35-38°C during addition.

[0075] 6) Add fragrance and moisturizer

[0076] Perform as in step 6 of Example 1, but under light-protected conditions.

[0077] 7) Nitrogen-filled filling

[0078] Brown glass bottles were selected as the packaging containers. Before filling, the internal space of the bottle was purged with sterile nitrogen for 1–2 seconds to replace the oxygen, followed by rapid filling and immediate capping and sealing. Sampling tests showed that the headspace oxygen volume fraction after sealing was controlled to be ≤2%.

[0079] Example 3: Preparation method with the addition of metal ion control and chelating agents

[0080] Formula (for every 1000 mL, add to the formula based on Example 1):

[0081] EDTA-2Na: 0.05 g. Those skilled in the art can adjust the dosage of EDTA-2Na within the range of 0.02 to 0.10 g / 1000 mL to suit water quality with different metal ion contents.

[0082] The remaining components are the same as in Example 1.

[0083] Preparation steps:

[0084] 1) Purified water and equipment pretreatment

[0085] Purified water treated by reverse osmosis and EDI is used, with a total metal ion content not exceeding 10 μg / L. The inner surfaces of equipment such as mixing tanks and pipelines are electropolished and passivated.

[0086] 2) Syrup preparation

[0087] Following step 2 of Example 1, sucrose and caramel color were dissolved in boiling purified water; after complete dissolution, 0.05 g / 1000 mL of EDTA-2Na was added at 60–80°C and stirred until completely dissolved.

[0088] 3) 200-mesh filtration and cooling

[0089] Follow the steps in Example 1, step 3) to circulate the filter and cool it to below 40°C.

[0090] 4) Subsequent steps

[0091] Complete the main drug addition, pH adjustment, vitamin B12 addition, flavoring addition, mixing and filling according to steps 4) to 7) of Example 1.

[0092] Example 4: Preparation method using two-stage filtration and particulate control

[0093] Formula: Same as Example 1.

[0094] Preparation steps:

[0095] 1) Syrup preparation and first filtration

[0096] Perform steps 2) and 3) of Example 1, ensuring that the 200-mesh sieve is circulated and filtered at least twice.

[0097] 2) Cool, add main ingredient, adjust pH, add vitamin B12 and flavoring, add water.

[0098] Follow steps 4) to 6) of Example 1.

[0099] 3) Terminal microporous membrane filtration

[0100] The well-mixed drug solution is filtered at the terminal stage through a filter equipped with a polyethersulfone microporous membrane with a pore size of 0.45 μm. The filtration pressure is controlled at about 0.15 MPa. After filtration, the solution immediately proceeds to the filling process.

[0101] Example 5: Accelerated stability and clarity / particulate matter comparison test

[0102] I. Comparative Example 1: Traditional Preparation Method

[0103] Formula: Lysine hydrochloride: 60 g, Vitamin B12: 3 mg, Inositol: 10 g, Sodium benzoate: 5 g, Citric acid: 1.5 g, Lemon flavor: 6 g, Sucrose: 450 g, Caramel color: 0.5 g, Purified water: add to 1000 mL.

[0104] Preparation process:

[0105] Heat purified water to boiling, add sucrose, caramel color and sodium benzoate, and stir until dissolved;

[0106] Stop heating and allow to cool to approximately 60°C;

[0107] Add lysine hydrochloride, inositol, citric acid and vitamin B12 together to the mixing tank, without checking the pH, directly add purified water to 1000 mL, and stir for about 1 hour;

[0108] It is filled and sealed directly without filtration, and is operated under normal light conditions without nitrogen purging.

[0109] II. Accelerated Stability Test

[0110] ① Test sample

[0111] Sample A: Comparative Example 1 (Traditional Process).

[0112] Sample B: Example 1 (pH precision control + B12 added separately at low temperature + 200-mesh circulating filtration).

[0113] Sample C: Example 2 (based on B, with the addition of vacuum degassing, light protection, and nitrogen filling).

[0114] Sample D: Example 3 (based on B, with the addition of EDTA-2Na chelation).

[0115] Sample E: Example 4 (based on B, with the addition of 0.45 μm terminal filtration).

[0116] ② Test conditions:

[0117] Accelerated storage conditions: 40 ℃±2 ℃, relative humidity 75 %±5%, protected from light;

[0118] Time points: 0, 1, 3, 6 months;

[0119] Three parallel samples were taken at each time point for analysis.

[0120] ③ Measurement items and methods:

[0121] Vitamin B12 content: determined by high performance liquid chromatography (HPLC), with the retention rate calculated as 100% of the initial standard. HPLC detection conditions and system suitability: detection channel eSATIN-Ch1, injection volume 20.00 μL, run time 30.0 minutes; system suitability parameters are as follows: Figure 1 Based on the typical spectrum shown, peak 1 (retention time approximately 12.775 min) has a USP tailing factor of 1.80 and a theoretical plate number of approximately 5382; peak 2, the characteristic peak of vitamin B12 (retention time approximately 25.777 min), has a peak area of ​​1131523, a peak height of 7726 mV, a USP tailing factor of 1.90, and an EP theoretical plate number of approximately 782. Furthermore, the USP resolution between peak 2 and peak 1 is ≥5.0 (typical value 5.21), which meets the system suitability requirements.

[0122] Vitamin B12 content: determined by high performance liquid chromatography (HPLC), with the retention rate calculated as 100% of the initial label.

[0123] Lysine hydrochloride content: determined by HPLC or amino acid analysis.

[0124] pH: Measured using a calibrated pH meter;

[0125] Appearance and color: Visually inspect whether the solution is clear and transparent, and whether there is any precipitate or discoloration;

[0126] Dissolved oxygen / headspace oxygen (for some samples C only): Measured using a dissolved oxygen meter / headspace oxygen analyzer.

[0127] ④ HPLC chromatographic analysis ( Figure 1 ): Using the lysine inositol vitamin B12 oral solution prepared in Example 1 (sample B) as a representative sample, HPLC chromatograms were collected at the initial time point (0 months). Figure 1Sample number 260204, collected on March 5, 2026. The chromatogram showed that two main chromatographic peaks were detected within a 30-minute run: Peak 1 had a retention time of 12.775 min (area 118207, peak height 4625 mV, USP tailing factor 1.80, theoretical plate number 5382), corresponding to highly polar components such as lysine hydrochloride in the solution; Peak 2 had a retention time of 25.777 min (area 1131523, peak height 7726 mV, USP tailing factor 1.90, theoretical plate number 782), which is a characteristic peak of vitamin B12 (cyanocobalamin). The USP resolution between peak 2 and peak 1 was 5.21 (≥2.0), and the tailing factors were all in the range of 1.0 to 2.0. The system suitability fully meets the requirements, indicating that the vitamin B12 chromatographic peak in the preparation of this invention is symmetrical and the quantification is reliable. At the same time, the small peak group in the 4-8 min interval corresponds to excipients such as inositol and citric acid, and does not interfere with the main drug peak.

[0128] The results are shown in Table 1:

[0129] Table 1. Retention rate of vitamin B12 content under accelerated conditions (%)

[0130] As can be seen from Table 1:

[0131] In traditional process sample A, vitamin B12 degrades significantly under accelerated conditions, retaining only about 48% after 6 months. Using the basic process of this invention (sample B), through precise pH control and separate low-temperature addition of B12, the retention rate can be increased to about 84% after 6 months. Further introducing vacuum degassing + light protection + nitrogen filling (sample C) or EDTA-2Na chelation (sample D) can achieve a retention rate of over 85% after 6 months, with significantly improved stability. Terminal membrane filtration (sample E) has little impact on the retention rate of B12 content, but can significantly improve clarity and particulate levels.

[0132] III. Clarity and Insoluble Particle Test

[0133] Test method:

[0134] Clarity: Sample in a transparent colorimetric tube and observe with the naked eye against a black and white background to determine whether there are visible insoluble particles or turbidity; if necessary, a turbidimeter can be used to measure the NTU value.

[0135] Insoluble microparticles: Following the test method for insoluble microparticles in injections in the Chinese Pharmacopoeia, particles ≥10 μm and ≥25 μm were counted as relative comparison indicators for oral solutions.

[0136] The results are shown in Table 2:

[0137] Table 2. Comparison of clarity and insoluble particles (after 3 months of accelerated storage)

[0138] visible:

[0139] Sample A lacked a filtration process and contained obvious particles and turbidity.

[0140] After samples B to D were filtered through a 200-mesh cyclic filter, the clarity was significantly improved and the number of insoluble particles decreased significantly.

[0141] Sample E, with the addition of a 0.45 μm terminal membrane filtration to the 200-mesh circulating filtration, further reduced the particle number to a lower level and achieved the best clarity.

[0142] IV. Corrosion Resistance Test

[0143] To verify that the preservative efficacy could still be guaranteed when the amount of sodium benzoate was reduced from 5 g / 1000 mL to 4 g / 1000 mL and the pH was controlled at 4.0-4.5, a multi-dose oral formulation preservative efficacy test was conducted on sample A (Comparative Example 1) and sample B (Example 1).

[0144] Test method:

[0145] According to the requirements of the Chinese Pharmacopoeia for the preservative efficacy test of multi-dose oral preparations, designated challenge bacteria (such as Escherichia coli, Staphylococcus aureus, Candida albicans, Aspergillus niger, etc.) were inoculated, and the changes in total bacterial count were measured at 0, 7, 14, and 28 days.

[0146] result:

[0147] Sample A's total bacterial count within 28 days met the pharmacopoeia's preservative efficacy standards.

[0148] Sample B, with sodium benzoate dosage reduced to 4 g / 1000 mL, maintained its preservative efficacy within the optimal antibacterial range of 4.0–4.5, meeting pharmacopoeia requirements, and no preservative failure was observed.

[0149] This indicates that, under the process of the present invention, the amount of sodium benzoate used can be reduced without reducing the anti-corrosion effect, which is beneficial to improving the safety of children's medication.

[0150] V. Observation of pH and crystallization

[0151] In the above stability test, the presence or absence of lysine hydrochloride crystallization or precipitation in each group of samples was observed periodically:

[0152] When sample A (Comparative Example 1) was stored at accelerated temperature for 3 to 6 months, fine crystal deposits were visible at the bottom of some bottles, which were presumed to be precipitated lysine hydrochloride.

[0153] No visible crystals or precipitates were observed in samples B to E under the same conditions, indicating that controlling the pH in the range of 4.0 to 4.5 can effectively inhibit the precipitation of lysine.

[0154] Based on the experimental data above, it is evident that the present invention has significant advantages over traditional processes in terms of stability, anti-corrosion efficacy, and clarity, thus confirming the effectiveness and practicality of the technical solution of the present invention.

[0155] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any ordinary changes and substitutions made by those skilled in the art within the scope of the technical solution of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a lysine inositol vitamin B12 oral solution, characterized in that, Includes the following steps: (1) Add purified water to the mixing tank, heat to boiling, add the prescribed amount of sucrose and caramel color, boil to sterilize, and obtain syrup; (2) The syrup obtained in step (1) is filtered through a 200-mesh stainless steel screen at least twice to remove insoluble particles and then cooled to below 40°C. (3) Dissolve the prescribed amount of lysine hydrochloride, inositol and citric acid in 5-15L of purified water, add it to the syrup solution obtained in step (2), stir and mix, and test and adjust the amount of citric acid to control the pH of the solution at 4.0-4.5; (4) Dissolve vitamin B12 separately in 1 L of purified water, add it to the solution obtained in step (3) when the liquid temperature in the mixing tank does not exceed 40 ℃, and stir to mix; (5) Dilute lemon flavoring in 95% ethanol and add it to the solution obtained in step (4). Add purified water that has been boiled and cooled to 30-40°C to the target volume. Turn on the stirrer and circulation pump to mix for 30-50 minutes, and then fill and seal.

2. The preparation method according to claim 1, characterized in that, After step (2) and before step (3), the syrup is subjected to vacuum degassing. The degassing conditions are -0.07 to -0.09 MPa in the tank for 10 to 20 minutes.

3. The preparation method according to claim 1, characterized in that, Steps (3) to (5) are carried out under light-protected conditions, wherein the light intensity is not higher than 1000 lux and the mixing tank and infusion pipeline are made of opaque materials; before filling, the packaging container is purged with nitrogen for 1 to 3 seconds and the headspace oxygen volume fraction is not higher than 2% after sealing.

4. The preparation method according to claim 2, characterized in that, During the preparation of the syrup, 0.02–0.10 g of disodium ethylenediaminetetraacetate (EDTA) was added as a metal ion chelating agent. The purified water used was purified water treated by reverse osmosis and EDI, and its total metal ion content was not higher than 10 μg / L.

5. The preparation method according to claim 4, characterized in that, The aqueous solution of lysine hydrochloride, inositol and citric acid is a 3-10 times concentrated mother liquor. The mother liquor and syrup are mixed online on the production line by mass flow meter at a volume ratio of (7-10):

1. After mixing, vitamin B12 solution is added online downstream of the mixing pipeline and mixed evenly by static mixer.

6. The preparation method according to claim 5, characterized in that, After mixing in step (5), the resulting solution is filtered through a 0.45 μm microporous membrane at a pressure of 0.1–0.3 MPa to reduce the content of insoluble particles.

7. The preparation method according to claim 6, characterized in that, The lemon flavoring and 95% ethanol are added in a mass ratio of 1:(1000-1500) after dilution, so that the ethanol mass fraction in the final formulation is controlled within the range of 0.5-1.0%.

8. The preparation method according to claim 7, characterized in that, The formulation of the lysine inositol vitamin B12 oral solution per 1000 mL includes: 60 g lysine hydrochloride, 3 mg vitamin B12, 10 g inositol, 4 g sodium benzoate, 2 g citric acid, 7 g lemon flavoring, 500 g sucrose, 0.5 g caramel color, and purified water to 1000 mL.

9. A lysine inositol vitamin B12 oral solution, comprising per 1000 mL: 60 g lysine hydrochloride, 3 mg vitamin B12, 10 g inositol, 4 g sodium benzoate, 2 g citric acid, 7 g lemon flavoring, 500 g sucrose, and 0.5 g caramel color, diluted with purified water to 1000 mL, characterized in that... The pH of the oral solution is controlled between 4.0 and 4.5, and it is prepared by the method described in any one of claims 1 to 7.

10. The lysine inositol vitamin B12 oral solution according to claim 9, characterized in that, Under accelerated storage conditions of 40 ℃ and 75% relative humidity for 6 months, the vitamin B12 content retention rate is not less than 85% of the initial labeled amount, and the product is filtered through a 0.45μm microporous membrane.

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