A pediatric multivitamin injection and its preparation method

Abstract

This invention relates to a pediatric multivitamin injection and its preparation method, specifically to a stable aqueous solution containing fat-soluble and water-soluble vitamins and its preparation process. The main components of this injection consist of two sterile vials. The first vial contains 10 main components. The preparation method for the first vial employs drug inclusion technology, using surfactants to encapsulate the fat-soluble vitamins and disperse them into the water-soluble vitamin solution, followed by pH adjustment, filtration, and filling. The second vial contains 3 main components. The preparation method for the second vial includes: dissolving the main components with excipients and adding them to the system in a fixed order, filtration, and filling. The pediatric multivitamin injection prepared according to the formulation and preparation process of this invention not only significantly improves storage stability and compatibility stability but also reduces the use of stabilizers and excipients, reducing adverse clinical reactions, increasing medication safety, and improving clinical compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a pediatric multivitamin injection and its preparation method. Background Technology

[0002] Vitamins are a class of trace organic substances that the human body must obtain from food to maintain normal physiological functions. There are many types of vitamins, each with a different chemical structure. Most are components of coenzymes (or prosthetic groups) of certain enzymes. They are essential compounds for maintaining normal bodily growth (growth, health, reproduction, and production functions). Vitamins play a vital role in regulating human metabolism, promoting growth and development, and maintaining physiological functions. They are one of the essential nutrients for the human body. The daily requirement for vitamins is extremely small, but long-term deficiency can lead to vitamin deficiency diseases; while excessive intake can cause vitamin poisoning.

[0003] Parenteral nutrition is a method of nutritional support that provides children with calories, fluids, protein, carbohydrates, fats, vitamins, and minerals, either entirely or partially, via intravenous infusion when they cannot tolerate enteral feeding or cannot fully tolerate it. This is to meet the body's metabolic and growth needs. The European Union usually recommends that parenteral nutrition be supplemented via intravenous infusion. Vitamins need to be mixed with saline, glucose solution, amino acids, or fat emulsions before use. Therefore, the amount of vitamins in the infusion after mixing is often lower than the clinically required amount.

[0004] In pediatric patients, some newborns and other pediatric patients who cannot be fed orally, such as premature infants, especially those with extremely low birth weight, those with severe asphyxia, those with severe respiratory distress syndrome, newborns with congenital digestive tract malformations requiring surgery, those with necrotizing enterocolitis, those with intractable diarrhea, and those with extrauterine growth retardation, need to maintain the nutrients required for normal physiological activities and growth and development through parenteral nutrition, including water, glucose, amino acids, fat emulsions, electrolytes, vitamins, and trace elements.

[0005] Fat-soluble vitamins have extremely low solubility in water, so certain solubilization methods are required to co-dissolve them with water-soluble vitamins in aqueous systems. Although existing technologies use the addition of protective agents and antioxidants, this increases the safety risks of clinical use, and the stability of the product itself cannot be guaranteed, let alone the dosage required for clinical compatibility. The literature (Chen Yousheng, Zhang Jianhong. Research on improving the solubility of poorly soluble drugs [J]. Strait Pharmaceutical Journal, 2008, (07): 25-27.) discloses a method for solubilizing fat-soluble drugs in aqueous systems, such as the micelle method. However, this method is relatively general and does not solve the stability of fat-soluble components in aqueous systems. Patent literature CN101953840A discloses the use of carboxylated chitosan as a solubilizer to encapsulate fat-soluble vitamins into micelles, which dissolve in water, thus solving the problem of water instability of fat-soluble vitamins. However, in reality, this product is made into a solid powder through freeze-drying. The stability test is also conducted on the final solid powder product, which does not truly solve the stability of fat-soluble components in aqueous systems. Moreover, the freeze-drying process will greatly increase energy consumption, leading to an increase in production costs. To address stability issues, patent document CN104415041B added protective agents and antioxidants dimethyl isosorbide dimethylol and propyl benzoate to the formulation, resulting in a significantly higher amount of excipients. This not only increased the formulation cost but also made quality control more difficult. Furthermore, the added excipients do not comply with the relevant requirements of the "Guiding Principles for Pharmaceutical Development of Pediatric Drugs (Chemical Drugs) (Trial Implementation)," posing a potential safety hazard for clinical use. While CN102652744B states that no antioxidants are used, the preparation process employs terminal sterilization. However, the inventors have discovered through experiments that most vitamins are heat-labile, and high temperatures can degrade vitamins, reducing their content.

[0006] In summary, existing technologies have not solved the stability problem of fat-soluble vitamins in pediatric multivitamin injections in aqueous environments. The purpose of this invention is to develop a formulation and preparation process for a pediatric multivitamin injection, completely resolving the stability and compatibility issues of fat-soluble components in aqueous environments, reducing production costs, and achieving industrialization. Summary of the Invention

[0007] This invention provides a pediatric multivitamin injection for use as a parenteral nutrition supplement in pediatric patients aged 11 years and under. The product formulation has been determined to have stability suitable for clinical use based on guideline recommendations and systematic studies.

[0008] The prescription and micelle preparation process for pediatric multivitamin injection provided by this invention can produce micelles with a spherical main structure, ensuring good stability of the product after long-term storage and compatibility.

[0009] To achieve the above-mentioned technology, the research content of this invention is as follows:

[0010] (1) Based on the recommended intake of pediatric parenteral vitamins and the clinical compatibility study of products in the “European Guidelines for Parenteral and Enteral Nutrition” (Part A. CURRICULUM VITAE (CVA)[J]. Computer Science, 2000, 79: 164.) and the “Chinese Guidelines for Clinical Application of Pediatric Parenteral and Enteral Nutrition Support” (Cai Wei, Cao Yun, Chen Jie, et al. Pediatric Parenteral Nutrition Guidelines: Vitamins[J]. Journal of Clinical Pediatrics, 2021, 39(08):605-620.), the most stable prescription of the product was determined.

[0011] (2) The study found that in order to prepare a stable spherical micelle system, the volume ratio of lipid-soluble solution to water-soluble solution needs to be controlled within the range of 1.4% to 2.5% in the preparation process. Secondly, the preparation process should control the transfer of lipid-soluble solution to water-soluble solution. The micelles prepared according to this process are mainly spherical micelles, and the prepared products are stable.

[0012] The technical solution of this invention is as follows:

[0013] 1. According to the EU parenteral nutrition guidelines, the recommended daily supplementation dose of vitamin A for children is 697 μg / day (1278 μg / day vitamin A palmitate, 2323 IU / day vitamin A). For water-soluble vitamin A mixtures, infants require approximately 920 IU / kg of vitamin A intravenously daily. Based on an infant's weight, the daily requirement is 2700 IU of vitamin A. The EU parenteral nutrition guidelines state that daily supplementation of 7 mg / day of vitamin E for children under 11 years of age and infants has no effect; however, to protect liver function and better maintain health, it is recommended to increase the dose of vitamin E. For PN (Parenteral Nutrition), infants and children should use once daily, not exceeding 11 mg per day. Therefore, based on the guidelines, we designed and studied multiple product formulations, investigated the interactions between the main components, and screened the optimal product formulation based on the research data. The EU parenteral nutrition guidelines recommend the following data:

[0014]

[0015] ① Experimental studies have found that vitamin E in mixed fat-soluble components has a certain protective effect on vitamin A palmitate and vitamin D3. Increasing the amount of vitamin E significantly improves the stability of the mixed fat-soluble components, indicating that vitamin E plays an antioxidant protective role in fat-soluble materials. As the fat-soluble component increases, the proportion of solubilizer also needs to be increased. Studies have found that a weight ratio of vitamin E to vitamin A palmitate of 5.7 or higher exhibits good stability. At the same time, studies have found that a weight ratio of surfactant polysorbate 80 to fat-soluble components of 3.5 to 4.0 exhibits good solubilizing effect and optimal solution clarification effect. Below 3.5 or above 4.0, the opalescence of the solution increases significantly and the clarity deteriorates.

[0016] ②According to experimental research, there is a certain correlation between vitamin C and vitamin B1 in water-soluble materials. Increasing the proportion of vitamin C will improve the degradation impurities of vitamin C and vitamin B1, indicating that vitamin C plays a protective role in water-soluble components. The study found that when the weight ratio of vitamin C to vitamin B1 is maintained at 64.0-64.6:1, the impurity level of water-soluble mixed components is relatively low, and the stabilization effect is optimal.

[0017] ③ According to EU guidelines, parenteral nutrition solutions should be administered intravenously. These solutions need to be mixed with commercially available 0.9% sodium chloride solution, 5% glucose solution, amino acid solution, and fat emulsion solution, etc. Studies have found that the content of these nutrients is significantly reduced after being mixed with the above-mentioned solvents. In particular, vitamin C is significantly reduced in the above-mentioned solvents, with a decrease of 5% to 20%. Fat-soluble components also decrease significantly, with a decrease of about 4% to 10%. The reason for this is that after the spherical micelles are diluted with the mixed solution, the concentration of CMC changes, and the configuration of the micelles changes. They are no longer spherical and mostly become bilayers spread on the water-soluble surface. In this state, fat-soluble components are exposed and become unstable, and will degrade.

[0018] Based on compatibility studies and to meet the recommended dosage in EU clinical guidelines, the formulation of this product has been adjusted from the EU recommended dosage. The specific formulation ratios determined by the studies are shown in the table below:

[0019] First Ampoule Injection Product Formulation Ratio Table

[0020] Element Dosage Vitamin A palmitate 2400 IU~2700IU (1.32mg~1.49mg) <![CDATA[Vitamin K1]]> 0.208 mg~0.220 mg <![CDATA[Vitamin D3]]> 420~460IU Vitamin E 7.5 IU~11 IU Vitamin C 84.0 mg~96.0 mg <![CDATA[Vitamin B1 (calculated as thiamine)]]> 1.30 mg~1.50 mg Riboflavin phosphate sodium (calculated as riboflavin) 1.42 mg~1.51 mg Dextropanol 5.15 mg~5.40 mg <![CDATA[Vitamin B6]]> 1.03 mg~1.08 mg Niacinamide 17.51mg~18.36mg Polysorbate 80 31.6 mg~50.9 mg Hydrochloric acid and / or sodium hydroxide Appropriate amount Water for Injection Add to 4ml

[0021] Second Ampoule Injection Product Formulation Ratio Table

[0022] Element Dosage folic acid 147.0 μg~156.8 μg Biotin 21.0 μg~22.4 μg <![CDATA[Vitamin B 12 > 1.10μg~1.30μg Mannitol 70 mg~80 mg Sodium citrate and citric acid, or either one or both. Appropriate amount Water for Injection Add to 1ml

[0023] The study found that by fixing the pH adjuster sodium citrate in the second ampoule injection product formulation above to 0.60–0.80 mg, the pH value of the prepared product met the requirements.

[0024] This invention also provides a method for preparing the pediatric multivitamin injection, comprising the following steps:

[0025] (1) Preparation of the first ampoule injection (taking 50,000 vials, 200L as an example): Weigh out the prescribed amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and polysorbate 80 in sequence and place them in a container. Control the container temperature at 30-50℃ and mix for 20-120 minutes to obtain a lipid-soluble solution. Add water for injection at 20-40℃ to the container, with the amount added being 50%-90% of the total volume. Weigh out the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dextropanthenol, vitamin B6, and riboflavin sodium phosphate and add them to the above water for injection in sequence. Stir and dissolve completely under nitrogen protection. Adjust the pH to 4.0-7.5. Slowly add the lipid-soluble solution to the rapidly stirred water-soluble solution. Add water for injection to the total volume and stir until uniform. Detect dissolved oxygen not exceeding 3mg / L. Filter with a filter cartridge with a pore size of 0.22μm, fill with nitrogen (controlling headspace residual oxygen not exceeding 5.0%), and perform light inspection and leak detection to obtain the final product.

[0026] (2) Preparation of the second ampoule injection solution (taking 150,000 vials, 150L as an example): Add water for injection at 20-40℃ to the container, the amount added is 90% of the total volume, then weigh the prescribed amount of mannitol and add it to the above water for injection. After stirring and dissolving completely, weigh the prescribed amount of biotin, dissolve it completely in the solution prepared with the prescribed amount of sodium citrate, and transfer it to the above solution. The concentration of the sodium citrate solution is 38.95mg / ml. Weigh the prescribed amount of folic acid and add it to the above solution, then weigh the prescribed amount of vitamin B. 12 Dissolve the solution completely in 1L of water for injection at a temperature not exceeding 40℃, add it to the above solution, stir for 20-60 minutes under nitrogen protection until completely dissolved, adjust the pH to 5.0-8.0, add water for injection to the total volume, stir evenly, and test the dissolved oxygen to ensure it does not exceed 3mg / L. Filter the solution using a 0.22μm pore size filter, fill with nitrogen (controlling headspace residual oxygen to not exceed 5.0%), check for leaks, and perform a light inspection to obtain the final product.

[0027] The pediatric multivitamin injection and its preparation method provided by this invention produce the following beneficial effects:

[0028] 1) The clinical use of the product of this invention is more in line with the European Union's guidelines for parenteral nutrition and the recommended clinical dosage.

[0029] 2) The vitamin injection solution prepared by this invention exhibits high encapsulation efficiency of fat-soluble vitamins: Step one of the preparation method restricts the order of addition of fat-soluble vitamins and controls the volume ratio of fat-soluble solution to water-soluble vitamin solution within the range of 1.4% to 2.5%. The micelle configuration of the samples prepared according to the predetermined formula and process is mainly spherical, and the fat-soluble encapsulation efficiency is consistently above 90%. This solves the problem of easy depolymerization of columnar and layered micelles.

[0030] 3) The products prepared by this invention have more stable quality: First, accelerated stability testing results show that the content of fat-soluble vitamins is stable and meets the recommended clinical dosage range. Second, the products prepared by this invention, after accelerated 6-month testing, did not show a significant decrease in vitamin content after dilution with the compatibility solution, and the content of each vitamin still meets the recommended clinical dosage range.

[0031] 4) The excipients used in the formulation of this invention are simple, and no antioxidants or protective agents are used, thereby increasing the safety of clinical medication.

[0032] 5) The preparation process of this invention is simple, highly operable, energy-efficient, and low-cost, and the quality of samples prepared according to the established formula and process is more stable. Attached Figure Description

[0033] Figure 1 This is a micelle electron microscope image of Example 1 under a 100nm scale lens.

[0034] Figure 2 This is a micelle electron microscope image of Example 2 under a 100nm scale lens.

[0035] Figure 3 This is a micelle electron microscope image of Example 3 under a 100nm scale lens.

[0036] Figure 4 This is a micelle electron microscope image of Example 4 under a 100nm scale lens.

[0037] Figure 5 This is a micelle electron microscope image of Scale 1 under a 100nm scale lens. Detailed Implementation

[0038] The present invention will be further described below with reference to specific embodiments. The following description is only for explaining the present invention. The scope of protection of the present invention is not limited to these embodiments. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the scope of protection of the present invention.

[0039] The methods for determining the content of major fat-soluble and water-soluble vitamins in the composition of the present invention are as follows:

[0040] (1) Vitamin D3 detection method

[0041] The determination was performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), and the operation was carried out in the dark.

[0042] Chromatographic conditions and system suitability: The solution was packed with octadecylsilane-bonded silica gel (250 mm × 4.6 mm); the mobile phase A was methanol-acetonitrile-water solution, and the mobile phase B was acetonitrile-isopropanol, with gradient elution performed according to the table below; the detection wavelength was 265 nm; and the column temperature was 40 °C.

[0043] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 5 90 10 6 50 50 35 50 50 36 10 90 50 10 90 51 90 10 80 90 10

[0044] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the vitamin D3 content by peak area using the external standard method; each 1 IU is equivalent to 0.025 μg.

[0045] (2) Detection methods for vitamin E, vitamin K1 and vitamin A palmitate

[0046] Determine according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), operate in the dark, prepare fresh before use or use a low temperature injector.

[0047] Chromatographic conditions: Octadecylsilane-bonded silica gel (250 mm × 4.6 mm) was used as the stationary phase; methanol-acetonitrile-water solution was used as mobile phase A, and acetonitrile-isopropanol was used as mobile phase B, with gradient elution performed according to the table below; the detection wavelength was 270 nm; and the column temperature was 35 °C.

[0048] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 35 65 30 35 65 40 10 90 54 10 90 55 35 65 70 35 65

[0049] The system suitability requirements are that in the chromatogram of the reference solution, vitamin E, vitamin K1 and vitamin A palmitate should elute in sequence, the theoretical plate number calculated based on the vitamin A palmitate peak should be no less than 5000, and the resolution between each peak should meet the requirements.

[0050] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the equivalent of 1 IU of vitamin E and 0.55 μg of vitamin A palmitate by peak area using the external standard method.

[0051] (3) Method for determining vitamin C content

[0052] Vitamin C was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The procedure was carried out in the dark; the sample was prepared fresh immediately before use or a low-temperature injector was used.

[0053] Accurately measure 2 ml of the test solution and place it in a 100 ml volumetric flask. Add mobile phase A to dilute to the mark and shake well.

[0054] For the reference solution, accurately weigh an appropriate amount of vitamin C reference standard, dissolve it in mobile phase A, and quantitatively dilute it to prepare a solution containing approximately 0.4 mg of vitamin C per ml. Shake well.

[0055] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (4.6 mm × 250 mm column); 0.015 mol / L sodium pentanesulfonate solution was used as mobile phase A, and 0.015 mol / L sodium pentanesulfonate solution-acetonitrile (25:75) was used as mobile phase B, with gradient elution according to the table below; the detection wavelength was 210 nm; and the column temperature was 35 °C.

[0056] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 5 95 5 34 70 30 39 20 80 39.1 95 5 60 95 5

[0057] For the assay, accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method.

[0058] (4) The encapsulation rate assessment scheme is as follows:

[0059] ① Take a normal product liquid and test the concentration (content) of vitamin A palmitate, vitamin E, vitamin K1 and vitamin D3, and record it as C1 of each component.

[0060] ② Take a normal product liquid, place it in a 3KD ultrafiltration centrifuge tube, set the centrifuge speed to 4000G, centrifuge for 40 minutes, take the filtrate and test the concentration of unencapsulated vitamin A palmitate, vitamin E, vitamin K1 and vitamin D3, and record it as C2 of each component.

[0061] ③ Encapsulation ratio calculation formula:

[0062] Encapsulation efficiency = (C1 - C2) / C1 × 100%

[0063] In the following examples, the surfactant polysorbate in the first ampoule injection is preferably polysorbate 80(II); the cosolvent and stabilizer mannitol in the second ampoule injection is preferably injection grade mannitol.

[0064] In the following examples and comparative examples, the first ampoule injection solution was filled using a 5ml borosilicate glass ampoule, and the second ampoule injection solution was filled using a 2ml or 1ml borosilicate glass ampoule.

[0065] Examples 1-2: First Ampoule Formulation and Preparation Method

[0066] Element Dosage in Example 1 Example 2 Dosage Vitamin C 84.0 g 96.0 g <![CDATA[Vitamin B1]]> 1.30 g 1.50 g Riboflavin sodium phosphate 1.42 g 1.51 g <![CDATA[Vitamin B6]]> 1.03 g 1.08 g Niacinamide 17.51g 18.36g Dextropanol 5.15 g 5.40 g Vitamin A palmitate 2.4 million IU 2.7 million IU <![CDATA[Vitamin K1]]> 0.208 g 0.220 g Vitamin E 7500 IU 11000 IU <![CDATA[Vitamin D3]]> 420,000 IU 460,000 IU Polysorbate 80 31.6 g 50.9 g Sodium hydroxide Appropriate amount Appropriate amount Add water for injection to 4000ml 4000ml

[0067] 1000 samples were made.

[0068] Preparation methods of Examples 1 and 2 above:

[0069] Weigh out the prescribed amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and polysorbate 80 in sequence and place them in a container. Control the container temperature at 30–50°C and mix for 20–120 minutes to obtain a lipid-soluble solution. Add 50% of the total volume of water for injection at 20–40°C to the container. Weigh out the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dextropanthenol, vitamin B6, and riboflavin sodium phosphate and add them to the water for injection in sequence. Stir and dissolve completely under nitrogen protection. Adjust the pH to 4.0–7.5. Slowly add the lipid-soluble solution to the rapidly stirred water-soluble solution (the ratio of lipid-soluble volume to water-soluble volume is 2.5%). Add water for injection to the total volume and stir until homogeneous. Check that the dissolved oxygen does not exceed 3 mg / L. Filter the solution using a 0.22 μm pore size filter, fill with nitrogen (controlling headspace residual oxygen to not exceed 5.0%), and perform light inspection and leak detection to obtain the final product.

[0070] Electron micrographs show that the micelles of this product are predominantly spherical.

[0071] Examples 3-4: First Ampoule Formulation and Preparation Method

[0072] Element Example 3 Dosage Example 4 Dosage Vitamin C 84.0 g 96.0 g <![CDATA[Vitamin B1]]> 1.30 g 1.50 g Riboflavin sodium phosphate 1.42 g 1.51 g <![CDATA[Vitamin B6]]> 1.03 g 1.08 g Niacinamide 17.51g 18.36g Dextropanol 5.15 g 5.40 g Vitamin A palmitate 2.4 million IU 2.7 million IU <![CDATA[Vitamin K1]]> 0.208 g 0.220 g Vitamin E 7500 IU 11000 IU <![CDATA[Vitamin D3]]> 420,000 IU 460,000 IU Polysorbate 80 31.6 g 50.9 g Sodium hydroxide Appropriate amount Appropriate amount Add water for injection to 4000ml 4000ml

[0073] 1000 samples were made.

[0074] Preparation methods of Examples 3 and 4 above:

[0075] Weigh out the prescribed amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and polysorbate 80 in sequence and place them in a container. Control the container temperature at 30–50°C and mix for 20–120 minutes to obtain a lipid-soluble solution. Add 90% of the total volume of water for injection at 20–40°C to the container. Weigh out the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dextropanthenol, vitamin B6, and riboflavin sodium phosphate and add them to the water for injection in sequence. Stir and dissolve completely under nitrogen protection. Adjust the pH to 4.0–7.5. Slowly add the lipid-soluble solution to the rapidly stirred water-soluble solution (the ratio of lipid-soluble volume to water-soluble volume is 1.4%). Add water for injection to the total volume and stir until homogeneous. Check that the dissolved oxygen does not exceed 3 mg / L. Filter the solution using a 0.22 μm pore size filter, fill with nitrogen (controlling headspace residual oxygen to not exceed 5.0%), and perform light inspection and leak detection to obtain the final product.

[0076] Electron micrographs show that the micelles of this product are predominantly spherical.

[0077] Examples 5-6: Second Ampoule Formulation and Preparation Method

[0078] Second ampoule prescription:

[0079] Element Example 5 Dosage Example 6 Dosage folic acid 147.0 mg 156.8 mg Biotin 21.0 mg 22.4 mg <![CDATA[Vitamin B 12 > 1.10 mg 1.30 mg Sodium citrate (calculated as anhydrous form) 600 mg 800 mg Mannitol 70g 80g Add water for injection to 1000ml 1000ml

[0080] 1000 samples were made.

[0081] Preparation methods for the second ampoule (Examples 5 and 6, taking 150,000 ampoules, 150L as an example): Add water for injection at 20-40℃ to the container, the amount added being 90% of the total volume. Then weigh the prescribed amount of mannitol and add it to the above water for injection. After stirring and dissolving completely, weigh the prescribed amount of biotin and dissolve it completely in the solution prepared with the prescribed amount of sodium citrate. Transfer the solution to the above solution. The concentration of the sodium citrate solution is 38.95mg / ml. Weigh the prescribed amount of folic acid and add it to the above solution. Then weigh the prescribed amount of vitamin B... 12 Dissolve the solution completely in 1L of water for injection at a temperature not exceeding 40℃, add it to the above solution, stir for 20-60 minutes under nitrogen protection until completely dissolved, adjust the pH to 5.0-8.0, add water for injection to the total volume, stir evenly, and test the dissolved oxygen to ensure it does not exceed 3mg / L. Filter the solution using a 0.22μm pore size filter, fill with nitrogen (controlling headspace residual oxygen to not exceed 5.0%), check for leaks, and perform a light inspection to obtain the final product.

[0082] Comparative Example 1: First Ampoule Formulation and Preparation Method

[0083] Element Dosage Vitamin C 80.0 g <![CDATA[Vitamin B1]]> 1.20 g Riboflavin sodium phosphate 1.40 g <![CDATA[Vitamin B6]]> 1.00 g Niacinamide 17.00g Dextropanol 5.00 g Vitamin A palmitate 2.3 million IU <![CDATA[Vitamin K1]]> 0.200 g Vitamin E 7000 IU <![CDATA[Vitamin D3]]> 400,000 IU Polysorbate 80 50 g Sodium hydroxide Appropriate amount Add water for injection to 4000ml

[0084] Prepare 1000 samples (the above raw material quantities are from the FDA's 'INFUVITE PEDIATRIC' instruction manual).

[0085] The preparation method of Comparative Example 1 above:

[0086] Weigh out the prescribed amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and polysorbate 80 in sequence and place them in a container. Control the container temperature at 30–50°C and mix for 20–120 minutes to obtain a lipid-soluble solution. Add water for injection at 20–40°C to the container, with the amount added being 45% of the total volume. Weigh out the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dextropanthenol, vitamin B6, and riboflavin sodium phosphate, and add them sequentially to the water for injection. Stir and dissolve completely under nitrogen protection. Adjust the pH to 4.0–7.5. Slowly add the lipid-soluble solution to the rapidly stirred water-soluble solution (the ratio of lipid-soluble volume to water-soluble volume is 2.7%). Add water for injection to the total volume, stir and mix thoroughly. Filter with a 0.22μm pore size filter, fill with nitrogen, and inspect for leaks under light.

[0087] Electron micrographs show that the micelles of Comparative Example 1 are mainly rod-shaped or layered structures.

[0088] Comparative Example 2: Formulation and Preparation Method of the Second Ampoule

[0089] Second ampoule prescription:

[0090] Element Dosage folic acid 140.0 mg Biotin 20.0 mg <![CDATA[Vitamin B 12 > 1.00 mg Sodium citrate (calculated as anhydrous form) 600mg Mannitol 75g Add water for injection to 1000ml

[0091] Prepare 1000 samples (the above main component amounts are from the FDA's 'INFUVITE PEDIATRIC' instruction manual).

[0092] Preparation method of Comparative Example 2 (Second Ampoule): Add 20-40℃ water for injection to a container, the amount added being 90% of the total volume. Then weigh the prescribed amount of mannitol and add it to the above water for injection. After stirring and dissolving completely, weigh the prescribed amount of biotin and dissolve it completely in the solution prepared with the prescribed amount of sodium citrate. Transfer the solution to the above solution. The concentration of the sodium citrate solution is 38.95 mg / ml. Weigh the prescribed amount of folic acid and add it to the above solution. Then weigh the prescribed amount of vitamin B... 12 Dissolve completely in 1L of water for injection at a temperature not exceeding 40℃, add to the above solution, stir for 20-60 minutes under nitrogen protection until completely dissolved, adjust the pH to 5.0-8.0, add water for injection to the total volume, stir evenly, filter with a filter cartridge with a pore size of 0.22μm, fill with nitrogen, check for leaks, and inspect by light to obtain the product.

[0093] To verify the characteristics and practical effects of this invention, we conducted micelle morphology analysis on the samples and simultaneously examined the encapsulation efficiency of the samples in Examples 1, 2, 3, 4, and Comparative Example 1. We also investigated the accelerated stability of the samples from Examples 1, 2, 3, 4, and Comparative Example 1 by placing them at 25±2℃ for 6 months. Furthermore, we conducted compatibility studies on the samples with accelerated stability after 6 months.

[0094] Example 7 Encapsulation efficiency assessment

[0095] Encapsulation efficiency was investigated for Examples 1, 2, 3, 4, and Comparative Example 1, using the following investigation scheme:

[0096] ① Take a normal product liquid and test the concentration (content) of vitamin A palmitate, vitamin E, vitamin K1 and vitamin D3, and record it as C1 of each component.

[0097] ② Take a normal product liquid, place it in a 3KD ultrafiltration centrifuge tube, set the centrifuge speed to 4000G, centrifuge for 40 minutes, take the filtrate and test the concentration of unencapsulated vitamin A palmitate, vitamin E, vitamin K1 and vitamin D3, and record it as C2 of each component.

[0098] ③ Encapsulation ratio calculation formula

[0099] Encapsulation efficiency = (C1 - C2) / C1 × 100%

[0100] The results of the encapsulation efficiency tests for different embodiments and comparative samples are summarized below:

[0101] Serial Number Ingredient name Sample source Initial concentration (μg / ml) Filtrate concentration (μg / ml) Encapsulation rate (%) 1 Vitamin A palmitate Example 1 334 5 98.5 2 Vitamin A palmitate Example 2 373 4 98.9 3 Vitamin A palmitate Example 3 330 6 98.2 4 Vitamin A palmitate Example 4 369 6 98.4 5 Vitamin A palmitate Comparative Example 1 316 32 89.9 6 <![CDATA[Vitamin D3]]> Example 1 2.63 0 100.0 7 <![CDATA[Vitamin D3]]> Example 2 2.88 0.02 99.3 8 <![CDATA[Vitamin D3]]> Example 3 2.56 0.02 99.2 9 <![CDATA[Vitamin D3]]> Example 4 2.83 0.06 97.9 10 <![CDATA[Vitamin D3]]> Comparative Example 1 2.52 0.26 89.7 11 Vitamin E Example 1 1875 22 98.8 12 Vitamin E Example 2 2750 39 98.6 13 Vitamin E Example 3 1865 26 98.6 14 Vitamin E Example 4 2746 35 98.7 15 Vitamin E Comparative Example 1 1749 181 89.7 16 <![CDATA[Vitamin K1]]> Example 1 51.2 1.1 97.9 17 <![CDATA[Vitamin K1]]> Example 2 55.3 1.9 96.6 18 <![CDATA[Vitamin K1]]> Example 3 52.6 0.8 98.5 19 <![CDATA[Vitamin K1]]> Example 4 54.6 1.3 97.6 20 <![CDATA[Vitamin K1]]> Comparative Example 1 49.8 5.7 88.6

[0102] The above results indicate that micelle systems prepared with a volume ratio of lipid-soluble materials to water-soluble materials in the range of 1.4% to 2.5% are stable, and the encapsulation efficiency of lipid-soluble drugs is over 90%.

[0103] Example 8: Accelerated Testing

[0104] Samples from Examples 1, 2, 3, 4, and Comparative Example 1 were placed at 25±2℃ for 6 months. Samples were taken at 3 and 6 months to determine the content of fat-soluble vitamins (vitamin E, vitamin A palmitate, vitamin D3, and vitamin K1). The initial test result on day 0 was used as 100% as a reference. The content results of the samples after placement were calculated. The accelerated stability test results are shown in the table below:

[0105] Sample source Time (month) Vitamin E content (%) Vitamin A palmitate content (%) <![CDATA[Vitamin D3 content (%)]]> <![CDATA[Vitamin K1 content (%)]]> Example 1 3 99.8 98.5 98.0 99.7 Example 1 6 98.9 98.4 98.7 98.8 Example 2 3 99.8 98.3 98.5 100.0 Example 2 6 99.8 98.6 99.0 99.7 Example 3 3 99.2 98.9 98.5 99.2 Example 3 6 98.5 99.4 98.0 98.5 Example 4 3 99.4 98.1 98.2 99.1 Example 4 6 99.0 98.4 98.7 98.6 Comparative Example 1 3 95.6 92.6 95.3 94.6 Comparative Example 1 6 91.6 86.6 91.3 89.6

[0106] The above results indicate that the fat-soluble vitamin components in the samples of Examples 1, 2, 3, and 4 were stable compared with the control samples within 6 months of accelerated testing, and the content of each component in the sample of Examples met the requirements.

[0107] Example 9 Compatibility Study

[0108] The samples from June were accelerated and mixed with 0.9% sodium chloride and 5% glucose solutions, respectively, and the content of components in the mixed solutions was examined within 24 hours.

[0109] Results of accelerated sample compatibility tests (5% glucose compatibility) at 6 months for Examples 1, 4, and Comparative Example 1:

[0110] Sample source Time (h) Vitamin E content (mg) Vitamin A palmitate content (mg) <![CDATA[Content of vitamin D3 (μg)]]> Vitamin C content (mg) Example 1 0 7.48 1.32 10.53 85.03 Example 1 24 7.30 1.27 10.11 75.66 Example 4 0 11.09 1.50 11.52 96.86 Example 4 24 10.89 1.41 11.09 83.69 Comparative Example 1 0 6.41 1.095 9.12 71.25 Comparative Example 1 24 6.15 0.986 8.30 56.91

[0111] Results of accelerated sample compatibility tests (0.9% sodium chloride solution) over 6 months for Examples 1, 4, and Comparative Example 1:

[0112] Sample source Time (h) Vitamin E content (mg) Vitamin A palmitate content (mg) <![CDATA[Content of vitamin D3 (μg)]]> Vitamin C content (mg) Example 1 0 7.45 1.33 10.51 85.01 Example 1 24 7.29 1.28 10.21 79.12 Example 4 0 11.05 1.49 11.51 96.88 Example 4 24 10.90 1.44 11.16 90.09 Comparative Example 1 0 6.40 1.093 9.11 71.03 Comparative Example 1 24 6.14 0.979 8.29 56.81

[0113] According to the data in the two tables above, the samples prepared according to the prescriptions and processes established in Examples 1 and 4, after accelerated mixing in June, showed that the component content met the recommended clinical dosage range, and the stability after mixing was significantly better than that of the control sample 1.

[0114] Results of accelerated sample compatibility tests (5% glucose compatibility) at 6 months for Examples 5, 6, and Comparative Example 2:

[0115] Sample source Time (h) Folic acid content (μg) Biotin content (μg) <![CDATA[Vitamin B 12 Content (μg)]]> Example 5 0 148.3 21.1 1.11 Example 5 24 140.9 20.0 1.05 Example 6 0 157.3 22.4 1.32 Example 6 24 147.6 21.0 1.26 Comparative Example 2 0 133.6 19.1 0.95 Comparative Example 2 24 126.9 18.1 0.91

[0116] Results of accelerated sample compatibility tests (prepared with 0.9% sodium chloride solution) for Examples 5, 6, and Comparative Example 2 over 6 months:

[0117] Sample source Time (h) Folic acid content (μg) Biotin content (μg) <![CDATA[Vitamin B 12 Content (μg)]]> Example 5 0 147.6 21.3 1.10 Example 5 24 140.2 20.2 1.04 Example 6 0 156.2 22.1 1.30 Example 6 24 146.5 20.5 1.22 Comparative Example 2 0 132.8 18.8 0.94 Comparative Example 2 24 124.8 17.9 0.87

[0118] According to the data in the two tables above, the samples prepared according to the prescriptions and processes established in Examples 5 and 6, after accelerated preparation in June, showed that the component content met the recommended clinical dosage range, which was significantly better than that of Comparative Example 2.

[0119] The above description is only for explaining the present invention. The scope of protection of the present invention is not limited to these embodiments. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the scope of protection of the present invention.

Claims

1. A pediatric multivitamin injection solution, characterized in that: The pediatric multivitamin injection solution consists of two ampoules. Each 4 ml volume of the first ampoule contains the following components: Vitamin A palmitate 2400–2700 IU, Vitamin K1 0.208–0.220 mg, Vitamin D3 420–460 IU, Vitamin E 7.5–11 IU, Vitamin C 84.0–96.0 mg, Vitamin B1 (as thiamine) 1.30–1.50 mg, Riboflavin phosphate sodium (as riboflavin) 1.42–1.51 mg, Dextropanthenol 5.15–5.40 mg, Vitamin B6 1.03–1.08 mg, Nicotinamide 17.51–18.36 mg, Surfactant Polysorbate 80(II) 31.6–50.9 mg, pH adjusted to 4.0–7.5; Each 1 ml volume of the second ampoule contains… The volume contains the following components in the following amounts: folic acid 147.0–156.8 μg, biotin 21.0–22.4 μg, vitamin B12, and vitamin B22. 12 1.10–1.30 μg, mannitol 70–80 mg as a solubilizer and stabilizer, adjust pH to 5.0–8.0; In the first ampoule, the mass ratio of vitamin E to vitamin A palmitate is 5.7~7.4:1, the mass ratio of polysorbate 80(II) to fat-soluble vitamins is 3.5~4.0:1, and the mass ratio of vitamin C to vitamin B1 is 64.0~64.6:

1. The pH adjuster in the second ampoule injection solution is sodium citrate, and the mass of sodium citrate on anhydrous basis is 0.60–0.80 mg; The preparation method of the pediatric multivitamin injection includes the following steps: Step 1: Preparation of the first ampoule injection solution: Weigh out the prescribed amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and surfactant polysorbate 80 in sequence and place them in a container. Control the container temperature at 30-50℃ and mix for 20-120 min to obtain a lipid-soluble solution. Add water for injection at 20-40℃ to the container, the amount added being 50%-90% of the total volume. Weigh out the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dextropanthenol, vitamin B6, and riboflavin sodium phosphate, and add them to the above water for injection in sequence. Stir and dissolve completely under nitrogen protection. Adjust the pH to 4.0-7.

5. Slowly add the lipid-soluble solution to the rapidly stirred water-soluble solution. Add water for injection to the total volume. Before filling, control the dissolved oxygen to not exceed 3 mg / L. Filter with a 0.22 μm pore size filter, fill with nitrogen, control the headspace residual oxygen to not exceed 5.0% during the filling process, and perform light inspection and leak detection. The volume ratio of the fat-soluble solution to the water-soluble solution ranges from 1.4% to 2.5%. Step 2: Preparation of the second ampoule injection solution: Add water for injection at 20-40℃ to the container, the amount added being 90% of the total volume. Then weigh the prescribed amount of mannitol and add it to the above water for injection. After stirring and dissolving completely, weigh the prescribed amount of biotin and dissolve it completely in the solution prepared with the prescribed amount of sodium citrate. Transfer the solution to the above solution. The concentration of the sodium citrate solution is 38.95 mg / ml. Weigh the prescribed amount of folic acid and add it to the above solution. Then weigh the prescribed amount of vitamin B... 12 Dissolve the solution completely in 1 L of water for injection at a temperature not exceeding 40°C. Add the solution to the above solution and stir for 20–60 min under nitrogen protection until completely dissolved. Adjust the pH to 5.0–8.0, add water for injection to the total volume, and stir evenly. Before filling, control the dissolved oxygen to not exceed 3 mg / L. Filter the solution using a filter with a 0.22 μm pore size, fill with nitrogen, control the headspace residual oxygen to not exceed 5.0% during the filling process, and perform leak detection and light inspection.

2. The pediatric multivitamin injection solution according to claim 1, characterized in that: The micelles have a spherical structure, and the encapsulation rate of lipid-soluble components is over 90%.

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