Multi-vitamin injection for children and preparation method thereof

Abstract

The invention relates to a multivitamin injection for children and a preparation method thereof, in particular to a stable aqueous solution preparation containing fat-soluble vitamins and water-soluble vitamins and a preparation process thereof. The main components of the injection comprise two small sterile injection bottles, the first bottle contains 10 main components, and the preparation method of the first bottle comprises the following steps: wrapping fat-soluble vitamins with a surfactant by adopting a drug inclusion technology, dispersing the fat-soluble vitamins into a water-soluble vitamin solution, adjusting the pH value, filtering, filling and the like. The second bottle comprises three main components, and a preparation method of the second bottle comprises the following steps: dissolving the main components by adopting auxiliary materials, adding the main components into a system according to a fixed sequence, filtering, filling and the like. The multi-vitamin injection for children, prepared according to the prescription and the preparation process disclosed by the invention, not only can fully improve the storage stability and the compatibility stability, but also can reduce the use of stabilizer auxiliary materials, reduce clinical adverse reactions, increase the medication safety and improve the clinical use compliance.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a multiple vitamin injection for children and a preparation method thereof. Background Art

[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, and their chemical structures are different. Most of them are components of certain enzyme coenzymes (or prosthetic groups). They are essential compounds for maintaining normal growth (growth, health, reproduction, and production functions) of the body. Vitamins play an important role in regulating human material metabolism, promoting growth and development, and maintaining physiological functions. They are one of the important nutrients for the human body. The daily requirement of vitamins for the human body is extremely small, but if lacking for a long time, vitamin deficiency diseases may occur; while excessive intake may cause vitamin poisoning.

[0003] Parenteral nutrition support is a nutritional support method in which when a child cannot or cannot fully tolerate enteral feeding, calories, fluids, proteins, carbohydrates, fats, vitamins, and minerals are completely or partially supplied intravenously to meet the nutritional needs of the body's metabolism and growth and development. Usually, the European Union recommends intravenous infusion for parenteral nutrition supplementation. Vitamins need to be formulated with normal saline, glucose solution, amino acids, or fat emulsion, etc. Therefore, the amount of vitamins in the formulated infusion often falls below the clinically required amount.

[0004] In pediatric patients, for some neonates and other pediatric patients who cannot be orally fed, such as: premature infants, especially very low birth weight infants, severely asphyxiated infants, infants with severe respiratory distress syndrome, neonates with congenital digestive tract malformations who need surgical operations, infants with necrotizing enterocolitis, infants with intractable diarrhea, infants with extrauterine growth retardation, etc., parenteral nutrition is required to maintain the nutrients necessary for normal physiological activities and growth and development of the human body, including water, glucose, amino acids, fat emulsion, electrolytes, vitamins, and trace elements.

[0005] Because of their extremely low solubility in water, fat-soluble vitamins need to be solubilized and co-dissolved with water-soluble vitamins in an aqueous system using certain solubilization methods. Although existing technologies use the addition of protective agents and antioxidants, this increases the safety risks in clinical use, and the stability of the product itself cannot be guaranteed, let alone the dosage 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 methods for solubilizing fat-soluble drugs into an aqueous system, such as the micellization method. However, this method is rather general and does not solve the stability of fat-soluble components in an aqueous system. Patent document CN101953840A discloses using a solubilizer, carboxymethyl chitosan, to encapsulate fat-soluble vitamins to form micelles and dissolve them in water, solving the problem of the instability of the water solubility of fat-soluble vitamins. However, in reality, this product is made into a solid powder through a freeze-drying process, and the stability investigation in the accelerated test also examines the final solid powder product, which does not truly solve the stability of fat-soluble components in a water-soluble system, and the energy consumption of the freeze-drying process will increase significantly, resulting in an increase in production costs. Patent document CN104415041B adds protective agents and antioxidants, dimethyl isosorbide and propyl gallate, to the formulation to solve the stability problem. The added excipients are significantly more, which not only increases the cost of the preparation but also makes quality control more difficult. The added excipients do not meet the relevant requirements of the "Guiding Principles for the Pharmaceutical Development of Pediatric Use (Chemical Drugs) (Trial)", and there are potential safety hazards in clinical use. Although CN102652744B states that antioxidants are not used, the preparation process uses terminal sterilization. However, the inventor has found through experiments that most vitamins are thermally unstable, and high temperatures can cause vitamins to degrade and their content to decrease.

[0006] In summary, the existing technologies have not solved the stability problem of fat-soluble vitamins in pediatric multi-vitamin injection in an aqueous environment. The purpose of the present invention is to develop a prescription and preparation process for pediatric multi-vitamin injection to completely solve the stability of fat-soluble components in an aqueous environment and the compatibility stability, reduce production costs, and achieve industrialization. Summary of the Invention

[0007] The present invention provides a pediatric multi-vitamin injection as a parenteral nutritional supplement for pediatric patients aged 11 years and below. Based on guideline recommendations and systematic research, a product prescription with stability meeting clinical use has been determined.

[0008] The prescription and micelle preparation process of the pediatric multi-vitamin injection provided by the present invention can form micelles with a spherical configuration as the main body, ensuring good stability of the product after long-term storage and compatibility.

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

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

[0011] (2) It was found that in the preparation process of a stable micelle system with a spherical configuration, the volume ratio of the lipophilic solution to the water-soluble solution needs to be controlled within the range of 1.4% - 2.5%. Secondly, in the preparation process, the transfer of the lipophilic solution into the water-soluble solution is controlled. The micelles prepared according to this process are mainly micelles with a spherical configuration, and the prepared product is stable.

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

[0013] 1. According to the recommendations of the EU Parenteral Nutrition Guidelines (the daily supplementary dose of vitamin A for children is 697 μg / day (1278 μg / day of vitamin A palmitate, 2323 IU / day of vitamin A). For the water-soluble mixture of vitamin A, infants are intravenously injected with approximately 920 IU / kg of vitamin A per day. Calculated based on the infant's weight, 2700 IU of vitamin A is required per day. The EU Parenteral Nutrition Guidelines state that there is no impact on children under 11 years old and infants with a daily supplementary dose of 7 mg / day of vitamin E. However, to protect liver function and maintain a better state, it is recommended to increase the dose of vitamin E. PN is used once a day for infants and children, not exceeding 11 mg per day. Therefore, based on the guidelines' recommendations, we designed and studied multiple groups of product formulation compositions, studied the interactions between the main components of the products, and screened the best product formula according to the research data. The recommended data of the EU Parenteral Nutrition Guidelines are as follows in the table:

[0014]

[0015] ① According to experimental research, it is found that vitamin E in the mixed fat-soluble components has a certain protective effect on vitamin A palmitate and vitamin D3. Increasing the amount of vitamin E will significantly improve the stability of the mixed fat-soluble components, indicating that vitamin E plays an antioxidant protective role in fat-soluble materials. As the proportion of fat-soluble components increases, the proportion of solubilizer required also needs to be increased. The research shows that when the weight ratio of vitamin E to vitamin A palmitate is 5.7 or above, it exhibits good stability. At the same time, it is found that when the weight ratio of the surfactant polysorbate 80 to the fat-soluble components is 3.5 - 4.0, it shows good solubilization effect and the best solution clarity effect. When it is lower than 3.5 or higher than 4.0, the opalescence of the solution will significantly increase and the clarity will deteriorate.

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

[0017] ③ According to the EU guidelines, parenteral nutrition solutions are required to be administered by intravenous infusion and need to be compatible with commercially available 0.9% sodium chloride solution, 5% glucose solution, amino acid solution, fat emulsion solution, etc. The research shows that after the above nutritional components are formulated into infusions with the compatible solvents, the component content decreases significantly. In particular, vitamin C decreases significantly in the above compatible solvents, with a decrease of 5% - 20%. The fat-soluble components also decrease significantly, with a decrease of about 4% - 10%. The reason for the research is that after the spherical micelles are diluted by the compatible solution, the CMC concentration changes, and the configuration of the micelles changes from the spherical configuration and mostly becomes a bilayer lying flat on the water-soluble surface. In this state, the fat-soluble components are exposed and the fat-soluble components are no longer stable and will degrade.

[0018] According to the results of the compatibility study and to meet the recommended doses in the EU clinical guidelines, the prescription of this product has been adjusted based on the EU recommended doses. The specific formulated ratios determined by the research are as follows in the table:

[0019] Product Formulation Ratio Table of the First Ampoule Injection

[0020] Ingredient Dosage Vitamin A Palmitate 2400 IU - 2700 IU (1.32 mg - 1.49 mg) <![CDATA[Vitamin K1]]> 0.208 mg - 0.220 mg <![CDATA[Vitamin D3]]> 420 - 460 IU 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 Sodium Phosphate (calculated as riboflavin) 1.42 mg - 1.51 mg Dexpanthenol 5.15 mg - 5.40 mg <![CDATA[Vitamin B6]]> 1.03 mg - 1.08 mg Nicotinamide 17.51 mg - 18.36 mg Polysorbate 80 31.6 mg - 50.9 mg Hydrochloric Acid and / or Sodium Hydroxide Appropriate amount Water for Injection To make 4 ml

[0021] Product Formulation Ratio Table of the Second Ampoule Injection

[0022] Ingredient Dosage Folic Acid 147.0 μg - 156.8 μg Biotin 21.0 μg - 22.4 μg <![CDATA[Vitamin B 12 > 1.10 μg - 1.30 μg Mannitol 70 mg - 80 mg Sodium Citrate, Citric Acid, either one or both Appropriate amount Water for Injection To make 1 ml

[0023] The research shows that: by fixing the pH regulator sodium citrate in the product formulation of the second ampoule injection in the table at 0.60 - 0.80 mg, the pH value of the prepared product meets the requirements.

[0024] The present invention also provides a preparation method for the multi-vitamin injection for children, comprising the following steps:

[0025] (1) Preparation of the first ampoule injection (taking 50,000 vials and 200 L as an example): Weigh the prescription amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and polysorbate 80 in sequence and place them in a container. Control the temperature of the container at 30-50 °C and mix for 20-120 min to obtain a fat-soluble solution. Add injection water at 20-40 °C to the container, and the added amount is 50%-90% of the total volume. Weigh the prescription amounts of vitamin C, vitamin B1, nicotinamide, dexpanthenol, vitamin B6, and riboflavin sodium phosphate, and add them to the above injection water in sequence. Stir and dissolve completely under nitrogen protection, adjust the pH to 4.0-7.5, slowly add the fat-soluble solution to the rapidly stirred water-soluble solution, make up the injection water to the total volume, stir and mix evenly, detect that the dissolved oxygen does not exceed 3 mg / L, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen (control the residual oxygen in the headspace not to exceed 5.0%), perform lamp inspection and leak detection to obtain the product.

[0026] (2) Preparation of the second ampoule injection (taking 150,000 vials and 150 L as an example): Add injection water at 20-40 °C to the container, and the added amount is 90% of the total volume. Then weigh the prescription amount of mannitol and add it to the above injection water. After stirring and dissolving completely, weigh the prescription amount of biotin, dissolve it completely with the solution prepared with the prescription amount of sodium citrate, and transfer it to the above solution. The concentration of the sodium citrate solution is 38.95 mg / ml. Weigh the prescription amount of folic acid and add it to the above solution. Then weigh the prescription amount of vitamin B 12 , dissolve it completely with 1 L of injection water not exceeding 40 °C, add it to the above solution, stir under nitrogen protection for 20-60 min until completely dissolved, adjust the pH to 5.0-8.0, make up the injection water to the total volume, stir evenly, detect that the dissolved oxygen does not exceed 3 mg / L, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen (control the residual oxygen in the headspace not to exceed 5.0%), perform leak detection and lamp inspection to obtain the product.

[0027] The beneficial effects of the multi-vitamin injection for children and its preparation method provided by the present invention are as follows:

[0028] 1) The product of the present invention is more in line with the clinical use dosage guided by the EU parenteral nutrition guidelines during clinical use.

[0029] 2) The vitamin injection prepared by the present invention has a high encapsulation rate of fat-soluble vitamins: In the first step of the preparation method, the addition sequence of fat-soluble vitamins is restricted, and the volume ratio of the fat-soluble solution to the water-soluble vitamin solution is controlled within the range of 1.4% - 2.5%. The main micelle configuration of the sample prepared according to the established prescription and process is a spherical structure, and the measured fat-soluble encapsulation rate is above 90%. This solves the problem that columnar and lamellar micelles are prone to depolymerization.

[0030] 3) The product prepared by the present invention has more stable quality: First, the results of the accelerated stability study of the sample show that the content of fat-soluble vitamins is stable and meets the recommended clinical dosage range. Second, for the sample of the product prepared by the present invention after 6 months of accelerated study, there is no obvious decrease in the 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 prescription of the present invention are simple, without using antioxidants and protectants, thereby increasing the safety of clinical medication.

[0032] 5) The preparation process of the present invention is simple, highly operable, energy-consuming less, and low-cost. The quality of the sample prepared according to the established prescription and process is more stable. Description of the Drawings

[0033] Figure 1 It is the electron micrograph of the micelles of Example 1 under a 100nm scale lens.

[0034] Figure 2 It is the electron micrograph of the micelles of Example 2 under a 100nm scale lens.

[0035] Figure 3 It is the electron micrograph of the micelles of Example 3 under a 100nm scale lens.

[0036] Figure 4 It is the electron micrograph of the micelles of Example 4 under a 100nm scale lens.

[0037] Figure 5 It is the electron micrograph of the micelles of Comparative Example 1 under a 100nm scale lens. Detailed Embodiments

[0038] The following further describes the present invention in combination with specific embodiments. The following description is only for explaining the present invention, and the protection scope 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 protection scope of the present invention.

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

[0040] (1) Detection method for vitamin D3

[0041] Determination was carried out with reference to the high performance liquid chromatography method (General Principles 0512, Section IV, Chinese Pharmacopoeia 2020 Edition), and the operation was carried out under light protection.

[0042] Chromatographic conditions and system suitability solution: Octadecylsilane chemically bonded silica gel was used as the filler (250 mm × 4.6 mm); methanol-acetonitrile-aqueous solution was used as mobile phase A, and acetonitrile-isopropanol was used as mobile phase B, and gradient elution was carried out according to the following table; the detection wavelength was 265 nm; 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] Assay method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram. Calculated by the external standard method based on the peak area, 1 IU of vitamin D3 is equivalent to 0.025 μg.

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

[0046] Determination was carried out with reference to the high performance liquid chromatography method (General Principles 0512, Section IV, Chinese Pharmacopoeia 2020 Edition), and the operation was carried out under light protection. Prepare freshly before use or use a low-temperature injector.

[0047] Chromatographic conditions: Octadecylsilane chemically bonded silica gel was used as the filler (250 mm × 4.6 mm); methanol-acetonitrile-aqueous solution was used as mobile phase A, and acetonitrile-isopropanol was used as mobile phase B, and gradient elution was carried out according to the following table; the detection wavelength was 270 nm; 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] System suitability requirements: In the chromatogram of the reference solution, vitamin E, vitamin K1 and vitamin A palmitate elute in sequence. The theoretical plate number calculated based on the vitamin A palmitate peak should be not less than 5000, and the resolution between each peak should meet the requirements.

[0050] Assay method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram. Calculated by the external standard method based on the peak area, 1 IU of vitamin E is equivalent to 1 mg, and 1 IU of vitamin A palmitate is equivalent to 0.55 μg.

[0051] (3)Method for the content of vitamin C

[0052] Vitamin C was determined by the high performance liquid chromatography method (General Principles 0512, Section IV, Chinese Pharmacopoeia 2020 Edition). The operation was carried out under light protection. Prepare freshly before use or use a low-temperature injector.

[0053] Test solution: Accurately measure 2 ml of this product solution, place it in a 100-ml volumetric flask, dilute it to the mark with mobile phase A, and shake well.

[0054] Reference solution: Take an appropriate amount of vitamin C reference substance, accurately weigh it, dissolve it with mobile phase A and quantitatively dilute it to prepare a solution containing about 0.4 mg of vitamin C per 1 ml, and shake well.

[0055] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (chromatographic column of 4.6 mm × 250 mm); use 0.015 mol / L sodium pentanesulfonate solution as mobile phase A, and use 0.015 mol / L sodium pentanesulfonate solution - acetonitrile (25:75) as mobile phase B, and perform gradient elution according to the following table; the detection wavelength is 210 nm; the column temperature is 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] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate according to the external standard method with the peak area.

[0058] (4)The encapsulation efficiency investigation plan is as follows:

[0059] ① Take the normal product feed liquid, detect the concentrations (contents) of vitamin A palmitate, vitamin E, vitamin K1, and vitamin D3, and record them as C1 of each component.

[0060] ② Take the normal product feed liquid, place it in a 3KD ultrafiltration centrifugal tube, set the centrifuge speed at 4000G, centrifuge for 40 min, take the filtrate and detect the concentrations of unencapsulated vitamin A palmitate, vitamin E, vitamin K1, and vitamin D3, and record them as C2 of each component.

[0061] ③ Encapsulation efficiency 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 is filled in a 5-ml medium-borosilicate glass ampoule bottle, and the second ampoule injection is filled in a 2-ml medium-borosilicate glass ampoule bottle or a 1-ml medium-borosilicate glass ampoule bottle.

[0065] Examples 1 - 2 Prescription and preparation method of the first ampoule

[0066] Ingredient Dosage in Example 1 Dosage in Example 2 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 Nicotinamide 17.51g 18.36g Dexpanthenol 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]]> 420000 IU 460000 IU Polysorbate 80 31.6 g 50.9 g Sodium Hydroxide Appropriate amount Appropriate amount Water for Injection added to 4000ml 4000ml

[0067] Prepare 1000 samples.

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

[0069] Weigh 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 temperature of the container at 30 - 50 °C and mix for 20 - 120 min to obtain a fat-soluble solution. Add injection water at 20 - 40 °C to the container, with the added amount being 50% of the total volume. Weigh the prescribed amounts of vitamin C, vitamin B1, niacinamide, dexpanthenol, vitamin B6, and riboflavin sodium phosphate, and add them to the above injection water in sequence. Stir and dissolve completely under nitrogen protection, adjust the pH to 4.0 - 7.5, slowly add the fat-soluble solution to the rapidly stirred water-soluble solution (the volume ratio of the fat-soluble solution to the water-soluble solution is 2.5%), make up the injection water to the total volume, stir and mix evenly, detect that the dissolved oxygen does not exceed 3 mg / L, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen (control the residual oxygen in the headspace not to exceed 5.0%), perform lamp inspection and leak detection to obtain the product.

[0070] It can be seen from the electron microscope photos that the micelle configuration of this product is mainly spherical.

[0071] Prescription and preparation method of the first ampoule in Examples 3 - 4

[0072] Ingredient Dosage in Example 3 Dosage in Example 4 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 Nicotinamide 17.51g 18.36g Dexpanthenol 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]]> 420000 IU 460000 IU Polysorbate 80 31.6 g 50.9 g Sodium Hydroxide Appropriate amount Appropriate amount Water for Injection added to 4000ml 4000ml

[0073] Prepare 1000 samples.

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

[0075] Weigh 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 temperature of the container at 30 - 50 °C and mix for 20 - 120 min to obtain a fat-soluble solution. Add injection water at 20 - 40 °C to the container, with the added amount being 90% of the total volume. Weigh the prescribed amounts of vitamin C, vitamin B1, niacinamide, dexpanthenol, vitamin B6, and riboflavin sodium phosphate, and add them to the above injection water in sequence. Stir and dissolve completely under nitrogen protection, adjust the pH to 4.0 - 7.5, slowly add the fat-soluble solution to the rapidly stirred water-soluble solution (the volume ratio of the fat-soluble solution to the water-soluble solution is 1.4%), make up the injection water to the total volume, stir and mix evenly, detect that the dissolved oxygen does not exceed 3 mg / L, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen (control the residual oxygen in the headspace not to exceed 5.0%), perform lamp inspection and leak detection to obtain the product.

[0076] It can be seen from the electron microscope photos that the micelle configuration of this product is mainly spherical.

[0077] Example 5-6 Second Ampoule Prescription and Preparation Method

[0078] Second Ampoule Prescription:

[0079] Ingredient Dosage in Example 5 Dosage in Example 6 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) 600 mg 800 mg Mannitol 70g 80g Water for Injection added to 1000ml 1000ml

[0080] 1000 samples are prepared.

[0081] Second Ampoule Preparation Method for Example 5 and Example 6 (taking 150,000 pieces and 150L as an example): Add injection water at 20 - 40°C into the container, and the added amount is 90% of the total volume. Then weigh the prescribed amount of mannitol and add it into the above injection water. After stirring until completely dissolved, weigh the prescribed amount of biotin, and after completely dissolving it with the solution prepared with the prescribed amount of sodium citrate, transfer it into 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 into the above solution. Then weigh the prescribed amount of vitamin B 12 , dissolve it completely with 1L of injection water not exceeding 40°C, add it into the above solution, stir for 20 - 60 min under nitrogen protection until completely dissolved, adjust the pH to 5.0 - 8.0, supplement injection water to the total volume, stir evenly, detect that the dissolved oxygen does not exceed 3 mg / L, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen (control the residual oxygen in the headspace not to exceed 5.0%), leak check, and lamp inspection to obtain the product.

[0082] Comparative Example 1 First Ampoule Prescription and Preparation Method

[0083] Ingredient Dosage Vitamin C 80.0 g <![CDATA[Vitamin B1]]> 1.20 g Riboflavin Sodium Phosphate 1.40 g <![CDATA[Vitamin B6]]> 1.00 g Nicotinamide 17.00g Dexpanthenol 5.00 g Vitamin A Palmitate 2.3 million IU <![CDATA[Vitamin K1]]> 0.200 g Vitamin E 7000 IU <![CDATA[Vitamin D3]]> 400000 IU Polysorbate 80 50 g Sodium Hydroxide Appropriate amount Water for Injection added to 4000ml

[0084] Prepare 1000 samples (the source of the above raw material amounts is the 'INFUVITE PEDIATRIC' instruction manual published by the FDA).

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

[0086] Weigh 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 min to obtain a fat-soluble solution; add injection water at 20 - 40°C into the container, and the added amount is 45% of the total volume. Weigh the prescribed amounts of vitamin C, vitamin B1, nicotinamide, dexpanthenol, vitamin B6, and riboflavin sodium phosphate according to the prescription, and add them into the above injection water in sequence. Stir until completely dissolved under nitrogen protection, adjust the pH to 4.0 - 7.5, slowly add the fat-soluble solution into the rapidly stirred water-soluble solution (the ratio of the fat-soluble volume to the water-soluble volume is 2.7%), supplement injection water to the total volume, stir and mix evenly, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen, lamp inspection, and leak check to obtain the product.

[0087] It can be seen from the electron microscope photos that the micelle configuration of the product of Comparative Example 1 is mainly rod-shaped or lamellar structures.

[0088] Comparative Example 2 Second Ampoule Prescription and Preparation Method

[0089] Second Ampoule Prescription:

[0090] Ingredient Dosage Folic Acid 140.0 mg Biotin 20.0 mg <![CDATA[Vitamin B 12 > 1.00 mg Sodium Citrate (calculated as anhydrous) 600 mg Mannitol 75g Water for Injection added to 1000ml

[0091] 1000 samples were prepared (the amounts of the above main components were sourced from the 'INFUVITE PEDIATRIC' instructions published by the FDA).

[0092] Second Ampoule Preparation Method of Comparative Example 2: Add injection water at 20 - 40°C to the container, with the addition amount being 90% of the total volume. Then weigh the prescribed amount of mannitol and add it to the above injection water. After stirring until completely dissolved, weigh the prescribed amount of biotin and dissolve it completely with the solution prepared from the prescribed amount of sodium citrate, and then transfer it 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 it completely with 1 L of injection water not exceeding 40°C, add it to the above solution, stir under nitrogen protection for 20 - 60 min until completely dissolved, adjust the pH to 5.0 - 8.0, supplement injection water to the total volume, stir evenly, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen, leak check, and lamp check to obtain the product.

[0093] To test the characteristics and actual effects of the present invention, we conducted the detection of the micelle morphology of the samples. Synchronously, we investigated the encapsulation efficiency of the samples in Example 1, Example 2, Example 3, Example 4, and Comparative Example 1. And for the samples in Example 1, Example 2, Example 3, Example 4, and Comparative Example 1, the accelerated stability was investigated by placing them at 25 ± 2°C for 6 months. And the compatibility of the samples with accelerated stability for 6 months was investigated.

[0094] Example 7 Investigation of Encapsulation Efficiency

[0095] The encapsulation efficiency of Example 1, Example 2, Example 3, Example 4, and Comparative Example 1 was investigated, and the investigation plan was as follows:

[0096] ① Take the normal product liquid and detect the concentrations (contents) of vitamin A palmitate, vitamin E, vitamin K1, and vitamin D3, denoted as C1 of each component.

[0097] ② Take the normal product liquid, place it in a 3KD ultrafiltration centrifugal tube, set the centrifuge speed at 4000G, centrifuge for 40 min, take the filtrate and detect the concentrations of unencapsulated vitamin A palmitate, vitamin E, vitamin K1, and vitamin D3, denoted as C2 of each component.

[0098] ③ Encapsulation efficiency calculation formula

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

[0100] The summary results of the encapsulation efficiency investigation of samples in different examples and comparative examples are as follows:

[0101] Serial Number Ingredient Name Sample Source Initial Concentration (μg / ml) Filtrate Concentration (μg / ml) Entrapment Efficiency (%) 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 Control 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]]> Control 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 Control 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]]> Control Example 1 49.8 5.7 88.6

[0102] The above results show that the micelle system prepared with the volume ratio of lipophilic materials to hydrophilic materials in the range of 1.4% - 2.5% is stable, and the encapsulation efficiency of lipophilic drugs is above 90%.

[0103] Example 8 Accelerated test investigation

[0104] Samples of Example 1, Example 2, Example 3, Example 4 and Comparative Example 1 were placed at 25 ± 2°C for 6 months. Samples were taken at 3 months and 6 months respectively to determine the contents of lipophilic vitamins (vitamin E, vitamin A palmitate, vitamin D3, vitamin K1). Taking the detection on the initial 0 day as 100% as the reference, the content results of the samples after placement were calculated. The results of the accelerated stability experiment are shown in the following table:

[0105] Sample Source Time (months) 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 show that the lipophilic vitamin components in the samples of Example 1, Example 2, Example 3 and Example 4 are more stable than those in the comparative example samples during the 6 - month accelerated test, and the content indexes of each component in the example samples meet the requirements.

[0107] Example 9 Compatibility investigation

[0108] The samples after 6 - month acceleration were respectively combined with 0.9% sodium chloride and 5% glucose solution, and the contents of components in the combined solutions were investigated within 24 hours.

[0109] Results of the compatibility test of the 6 - month accelerated samples of Example 1, Example 4 and Comparative Example 1 (compatible with 5% glucose):

[0110] Sample source Time (h) Vitamin E content (mg) Vitamin A palmitate content (mg) <![CDATA[Vitamin D3 content (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 the compatibility test of the 6 - month accelerated samples of Example 1, Example 4 and Comparative Example 1 (0.9% sodium chloride solution):

[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 above two tables, it can be known that for the samples prepared according to the prescriptions and processes of Example 1 and Example 4, the component contents after compatibility of the 6 - month accelerated samples meet the recommended clinical dosage range, and the stability after compatibility is significantly better than that of the sample of Comparative Example 1.

[0114] Results of 6-month accelerated sample compatibility tests for Example 5, Example 6 and Comparative Example 2 (compatibility with 5% glucose):

[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 6-month accelerated sample compatibility tests for Example 5, Example 6 and Comparative Example 2 (compatibility with 0.9% sodium chloride solution):

[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 above two tables, for the samples prepared according to the prescriptions and processes of Example 5 and Example 6, the component contents after 6-month accelerated sample compatibility meet the recommended clinical dosage range, which is significantly better than that of Comparative Example 2.

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

Claims

1. A multiple vitamin injection for children, characterized in that: It consists of injections in two ampoules. In the first ampoule injection, the amounts of the following components contained in every 4 ml volume are: vitamin A palmitate 2,400 - 2,700 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 (calculated as thiamine) 1.30 - 1.50 mg, riboflavin sodium phosphate (calculated as riboflavin) 1.42 - 1.51 mg, dexpanthenol 5.15 - 5.40 mg, vitamin B6 1.03 - 1.08 mg, nicotinamide 17.51 - 18.36 mg, surfactant polysorbate 31.6 - 50.9 mg, and the pH is adjusted to 4.0 - 7.5; in the second ampoule injection, the amounts of the following components contained in every 1 ml volume are: folic acid 147.0 - 156.8 μg, biotin 21.0 - 22.4 μg, vitamin B 12 1.10 - 1.30 μg, solubilizer and stabilizer mannitol 70 - 80 mg, and the pH is adjusted to 5.0 - 8.

0.

2. The multi - vitamin injection for children according to claim 1, wherein: In the first ampoule injection, the surfactant polysorbate is polysorbate 80 (II), and the pH regulator is sodium hydroxide and / or hydrochloric acid; in the second ampoule injection, the cosolvent and stabilizer mannitol is injection-grade mannitol, and the pH regulator is selected from any one or both of sodium citrate and citric acid.

3. A multiple vitamin injection for children according to any one of claims 1-2, characterized in that: In the first ampoule injection, the pH regulator is sodium hydroxide, and in the second ampoule injection, the pH regulator is sodium citrate.

4. A multivitamin injection for children according to any one of claims 1-3, characterized in that: The mass ratio of vitamin E to vitamin A palmitate is (5.7 - 7.4):1, the mass ratio of polysorbate 80 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.

5. A pediatric multi-vitamin injection according to any one of claims 1-4, characterized in that: In the second ampoule injection, the pH regulator is sodium citrate, and the mass of sodium citrate is 0.60 - 0.80 mg.

6. A multivitamin injection for children according to any one of claims 1-5, characterized in that: The first ampoule injection uses a 5-ml medium-borosilicate glass ampoule bottle, and the second ampoule injection uses a 2-ml medium-borosilicate glass ampoule bottle or a 1-ml medium-borosilicate glass ampoule bottle.

7. The preparation method of a multivitamin injection for children according to any one of claims 1-6, characterized in that, It includes the following steps: Step 1, Preparation of the first ampoule injection: Weigh the prescription amounts of vitamin K1, vitamin E, vitamin A palmitate, vitamin D3, and the surfactant polysorbate 80 in sequence and place them in a container. Control the temperature of the container at 30 - 50 °C and mix for 20 - 120 min to obtain a fat-soluble solution; add injection water at 20 - 40 °C to the container, and the added amount is 50% - 90% of the total volume. Weigh the prescription amounts of vitamin C, vitamin B1, niacinamide, dexpanthenol, vitamin B6, and riboflavin sodium phosphate, and add them to the above injection water in sequence. Stir and dissolve completely under nitrogen protection, adjust the pH to 4.0 - 7.5, slowly add the fat-soluble solution to the rapidly stirred water-soluble solution, make up the injection water to the total volume, filter with a 0.22-μm pore size filter element, fill with nitrogen, perform lamp inspection, and leak detection to obtain it; Step 2. Preparation of the second ampoule injection: Add water for injection at 20 - 40°C into a container, with the added amount being 90% of the total volume. Then weigh the prescribed amount of mannitol and add it into the above-mentioned water for injection. After stirring until completely dissolved, weigh the prescribed amount of biotin, dissolve it completely with the solution prepared from the prescribed amount of sodium citrate, and transfer it into 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 into the above solution. Then weigh the prescribed amount of vitamin B 12 , dissolve it completely with 1 L of water for injection not exceeding 40°C, add it into the above solution, stir under nitrogen protection for 20 - 60 min until completely dissolved, adjust the pH to 5.0 - 8.0, supplement water for injection to the total volume, stir evenly, filter with a filter element with a pore size of 0.22 μm, fill with nitrogen, check for leaks, and perform lamp inspection to obtain the product; Before filling the liquid materials of the first ampoule injection and the second ampoule injection, control the dissolved oxygen, and control the headspace residual oxygen during the filling process.

8. According to step one in the preparation method according to claim 7, it is characterized in that: In the preparation method of the first ampoule injection, the volume ratio of the fat-soluble solution to the water-soluble solution is 1.4% - 2.5%.

9. The preparation method according to any one of claims 7-8, characterized in that: Before filling the liquid materials of the first ampoule injection and the second ampoule injection, control the dissolved oxygen not to exceed 3 mg / L, and control the headspace residual oxygen not to exceed 5.0% during the filling process.

10. A pediatric multivitamin injection prepared by the method according to any one of claims 7-9, characterized in that: The micelle configuration is a spherical structure, and the encapsulation efficiency of the micelle fat-soluble components is above 90%.

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