Vitamin DK oral liquid and preparation method thereof

Abstract

The invention provides a vitamin DK oral liquid and a preparation method thereof, and belongs to the technical field of pharmaceutical preparation processing. Medium chain triglyceride, butylated hydroxytoluene, vitamin D3 and vitamin K2 are mixed to serve as an oil phase, water, starch sodium octenylsuccinate and glycerin are mixed to serve as a water phase, the water phase is added into the oil phase, a glue solution and a concentrated solution are prepared respectively, and the vitamin DK nano-emulsion oral liquid is prepared under shearing and homogenizing. The prepared nano-emulsion is small in particle size and good in physical stability, the particle size is not obviously changed when the nano-emulsion is stored at different temperatures, the particle size is not obviously changed when the nano-emulsion is stored for a long time, and the nano-emulsion is good in stability and can be stored for a long time.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation processing, and in particular to a vitamin DK oral solution and a preparation method thereof. Background Art

[0002] As an aqueous solution dosage form, the development and use of vitamin DK oral solution has received widespread attention. However, there are some problems in the prior art that need to be solved. First, there are relatively few varieties of oral liquid preparations, because different vitamins combined together will produce higher stability requirements, and because fat-soluble vitamin oral liquid products are relatively single, many commonly used drugs with high clinical needs do not have suitable oral liquid preparations, so to a certain extent, it also restricts its development. The technical difficulties mainly include the solubility of the drug, the stability of the preparation, the safety of the excipients, and the compliance of the patient.

[0003] In terms of solubility issues, the solubility of the drug in oral liquid preparations needs to be considered to ensure the effective concentration and stability of the drug. The stability issue involves the physical and chemical stability of the preparation during storage and use. The safety of excipients is also a key point. The excipients used in children's oral liquid preparations need to ensure that they meet national requirements, including flavoring agents, preservatives and surfactants. In addition, medication compliance issues, such as the taste of the drug, the volume of administration, etc., will also affect the patient's compliance with medication and the therapeutic effect. The problems existing in the preparation of vitamin nanoemulsion oral solution in the prior art mainly include:

[0004] 1. Bioavailability problem: Fat-soluble vitamins have low solubility in water. When they are directly used in food, medicine and health products, the absorption and utilization rate of organisms is low, which affects their efficacy.

[0005] 2. Stability issues: Vitamins are easily degraded by light, high temperature or oxygen, and improving their stability is a technical challenge.

[0006] 3. High production cost: Some production processes require a high-pressure homogenizer to fully emulsify the vitamins. Excessively high temperatures during emulsification may damage the structure of the vitamins themselves. Cooling devices are also required, which increases equipment investment and production costs.

[0007] 4. High energy consumption: In some production processes, solvents such as vegetable oils need to be preheated before adding fat-soluble vitamins. Stirring and dissolving requires maintaining a high temperature, and then adding adjuvants, water, etc. to grind into an emulsion matrix, which consumes a lot of energy.

[0008] 5. Complicated process: Some production processes require physical treatment of vitamins, controlling the particle size below 100nm, and then adding solvents, water, preservatives, etc. The process is relatively complicated and the cost is high, making it difficult to sell and promote on a large scale in the market.

[0009] 6. Difficulty in large-scale production: Some production processes are difficult to scale up, such as water bath heating for pretreatment, which limits their large-scale application.

[0010] 7. Quality control challenges: Establishing accurate and reliable testing methods requires high quality control of preparations. It is necessary to test the dissolution, content and related substances, and study the physical and chemical properties of the preparations to ensure product quality.

[0011] 8. Physical stability of nanoemulsion: Although nanoemulsion is a kinetically stable system, under certain conditions, such as low temperature, its stability is poor and stratification may occur, resulting in the loss of its original excellent properties.

[0012] To solve these problems, it is necessary to improve the bioavailability, stability and production efficiency of vitamin nanoemulsion oral solution through technological innovation and improved production process, while reducing costs. Summary of the invention

[0013] The object of the present invention is to provide a vitamin DK oral liquid and a preparation method thereof, so as to solve the technical problems existing in the above-mentioned prior art.

[0014] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0015] The present invention provides a vitamin DK oral solution, which is composed of the following components in parts by weight:

[0016]

[0017]

[0018] The present invention also provides a method for preparing vitamin DK oral liquid, comprising the following steps:

[0019] (1) medium chain triglyceride and butylated hydroxytoluene are mixed in a water bath, and then vitamin D3 and vitamin K2 are added in sequence to obtain an oil phase after mixing;

[0020] (2) mixing water and sodium starch octenyl succinate in a water bath to obtain a sodium starch octenyl succinate solution, and adding glycerol to the sodium starch octenyl succinate solution and mixing to obtain an aqueous phase;

[0021] (3) adding part of the water phase to the oil phase and mixing to obtain colostrum;

[0022] (4) adding colostrum to the remaining aqueous phase, mixing, and then sequentially performing shear homogenization and high pressure homogenization to obtain an embedding emulsion;

[0023] (5) adding water to the colloidal microcrystalline cellulose, mixing the mixture and then shearing and emulsifying the mixture to obtain a colloidal solution;

[0024] (6) mixing water, sodium citrate, sucralose, sodium ascorbate and the embedding emulsion to obtain a concentrate;

[0025] (7) Mix water, fructose syrup and concentrated solution, add gelatin solution after filtering, and add water to make up the volume to obtain vitamin DK oral solution.

[0026] Furthermore, in step (1), the temperature of the water bath is 60-80°C, and the temperature for adding vitamin D3 is 30-50°C.

[0027] Furthermore, in the step (2), the mass ratio of water to sodium starch octenyl succinate is 3-4:3-4, the temperature of the water bath is 50-70° C., the mixing speed is 180-220 rpm, and the mixing time is 4-6 h.

[0028] Furthermore, in step (3), part of the aqueous phase accounts for 4 to 8% of the total mass of the aqueous phase, the mixing speed is 500 to 700 rpm, and the mixing time is 20 to 30 min.

[0029] Furthermore, in the step (4), the mixing speed is 500-700 rpm, the shear homogenization speed is 6000-8000 rpm, the shear homogenization time is 20-30 min; and the pressure of the high-pressure homogenization is 75-85 MPa.

[0030] Furthermore, in step (5), the mass ratio of colloidal microcrystalline cellulose to water is 0.8 to 1.2:9×10 4 ~1.1×10 5 ;

[0031] The mixing temperature is 80-90° C., and the mixing time is 30-40 min. The rotation speed of the shear emulsification is 10000-11000 rpm, and the shear emulsification time is 8-10 min.

[0032] Furthermore, in step (6), the mass ratio of water to sodium citrate is 200-300:0.4-0.8.

[0033] Furthermore, in the step (7), the mass ratio of water to fructose syrup is 550-650:8-10; and the vitamin DK oral liquid is filtered through a 200-300 mesh filter.

[0034] Beneficial effects of the present invention:

[0035] Principle of the present invention:

[0036] The medium-chain triglyceride (MCT) used in the oil phase of the present invention is a special oil, which is composed of medium-chain fatty acids (usually fatty acids containing 6 to 12 carbon atoms). The advantage is that the digestion and absorption process in the human body is different from that of long-chain triglycerides. It can quickly supply energy, does not need to be re-esterified in the small intestinal mucosal epithelial cells, can be directly absorbed, and enters the liver for metabolism through the portal vein. Butylated hydroxytoluene (BHT) is a commonly used antioxidant, which is added to the oil phase to extend the shelf life of oils and prevent oil oxidation. Vitamin D3 and vitamin K2 are two fat-soluble vitamins that can be dissolved in the oil phase, which helps to improve the nutritional value and stability of the product. The principle of mixing these ingredients as the oil phase is based on their mutual solubility and stability. MCT can be used as a base oil for the oil phase due to its low viscosity and high oxidation stability. BHT, as an antioxidant, helps to protect oils and other sensitive components from oxidation. Vitamin D3 and vitamin K2, as active ingredients, can be dissolved in the oil phase to ensure their effectiveness and stability in the final product.

[0037] The water phase is added with a highly safe emulsifying thickener, sodium starch octenyl succinate, which has good water solubility and stability and can improve the viscosity and stability of the product. Glycerin is a common polyol that can increase the viscosity of the water phase. Adding the water phase to the oil phase to prepare a glue or concentrate is based on the effect of the emulsifier. The emulsifier molecule has two ends, one hydrophilic and the other hydrophobic, which can mix the water phase and the oil phase to form a uniform emulsion. Emulsifiers can reduce the interfacial tension between oil and water, making them easier to mix and form a stable emulsion that is not easy to stratify and precipitate. In the oil / water emulsion, the hydrophilic carboxylic acid group and the lipophilic octenyl long chain of sodium starch octenyl succinate act on water and oil respectively, forming a tough film and improving the stability of the emulsion.

[0038] In the technical solution for preparing the vitamin DK nanoemulsion oral solution, compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. Improve bioavailability: Through nanoemulsion technology, fat-soluble vitamins such as vitamin D3 and vitamin K2 are converted into smaller nanoscale particles, which helps to improve their solubility and bioavailability in the body, so that they can be more effectively absorbed and utilized by the human body.

[0040] 2. Improved stability: Nanoemulsion systems generally have better physical and chemical stability due to their smaller droplet size and higher surface energy, which helps vitamins maintain their activity during storage and use.

[0041] 3. Protect vitamins from degradation: Vitamin D3 and vitamin K2 are easily degraded in the presence of light, high temperature or oxygen. Nanoemulsions can reduce the impact of these factors by providing a protective environment, thereby extending the shelf life of vitamins.

[0042] 4. Improve taste and appearance: Nanoemulsion technology can improve the taste and appearance of vitamin oral solution, making it more delicate and uniform, and increasing consumer acceptance.

[0043] 5. Easy preparation and administration: Nanoemulsions are easy to mix with other drug ingredients or excipients, which helps to prepare various dosage forms of drugs, such as oral solutions, capsules, etc., and also facilitates the control of dosage and administration methods.

[0044] 6. Reduce side effects: By improving the bioavailability and stability of vitamins, nanoemulsion technology helps reduce side effects that may result from excessive intake or uneven distribution.

[0045] 7. Improve therapeutic efficacy: Vitamins in nanoemulsion are more easily absorbed and can exert their biological effects more quickly, thereby improving the therapeutic effect.

[0046] These beneficial effects are based on the advantages of nanoemulsion technology in improving the stability and bioavailability of fat-soluble vitamins and protecting active ingredients. Through this technology, the role of vitamin D3 and vitamin K2 in the prevention and treatment of related diseases can be better exerted. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a graph showing the particle size detection results of the nanoemulsion prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0048] The present invention provides a vitamin DK oral solution, which is composed of the following components in parts by weight:

[0049]

[0050]

[0051] In the present invention, the content of the medium chain triglyceride is preferably 0.2 parts by mass.

[0052] In the present invention, the content of butylated hydroxytoluene is preferably 0.02 parts by mass.

[0053] In the present invention, the content of vitamin D3 is preferably within 8×10 -4 ~9×10 -4 share.

[0054] In the present invention, the content of vitamin K2 is preferably 0.19 parts by mass.

[0055] In the present invention, the content of sodium starch octenyl succinate is preferably 3.5 parts by mass.

[0056] In the present invention, the content of glycerol is preferably 2.5 parts by mass.

[0057] In the present invention, the content of the colloidal microcrystalline cellulose is preferably 0.9 to 1.1 parts by mass, and more preferably 1.0 part.

[0058] In the present invention, the content of sodium citrate is preferably 0.5 to 0.7 parts by mass, and more preferably 0.6 parts.

[0059] In the present invention, the content of sucralose is preferably 0.15 parts by mass.

[0060] In the present invention, the content of sodium ascorbate is preferably 0.15 parts by mass.

[0061] In the present invention, the content of the fructose-glucose syrup is preferably 9 to 10 parts by mass, and more preferably 9.5 parts by mass.

[0062] In the present invention, the water content is preferably 9×10 4 ~1.2×10 5 Parts, more preferably 1.0×10 5 share.

[0063] The present invention also provides a method for preparing vitamin DK oral liquid, comprising the following steps:

[0064] (1) medium chain triglyceride and butylated hydroxytoluene are mixed in a water bath, and then vitamin D3 and vitamin K2 are added in sequence to obtain an oil phase after mixing;

[0065] (2) mixing water and sodium starch octenyl succinate in a water bath to obtain a sodium starch octenyl succinate solution, and adding glycerol to the sodium starch octenyl succinate solution and mixing to obtain an aqueous phase;

[0066] (3) adding part of the water phase to the oil phase and mixing to obtain colostrum;

[0067] (4) adding colostrum to the remaining aqueous phase, mixing, and then sequentially performing shear homogenization and high pressure homogenization to obtain an embedding emulsion;

[0068] (5) adding water to the colloidal microcrystalline cellulose, mixing the mixture and then shearing and emulsifying the mixture to obtain a colloidal solution;

[0069] (6) mixing water, sodium citrate, sucralose, sodium ascorbate and the embedding emulsion to obtain a concentrate;

[0070] (7) Mix water, fructose syrup and concentrated solution, add gelatin solution after filtering, and add water to make up the volume to obtain vitamin DK oral solution.

[0071] In the present invention, the preparation of the oil phase is carried out under light protection.

[0072] In the present invention, in step (1), the temperature of the water bath is 60-80°C, preferably 65-75°C, and more preferably 70°C; the temperature for adding vitamin D3 is 30-50°C, preferably 35-45°C, and more preferably 40°C.

[0073] In the present invention, in the step (2), the mass ratio of water to sodium starch octenyl succinate is 3-4:3-4, preferably 3.5:3.5; the temperature of the water bath is 50-70°C, preferably 55-65°C, and more preferably 60°C; the mixing speed is 180-220rpm, preferably 190-210rpm, and more preferably 200rpm; the mixing time is 4-6h, preferably 5h.

[0074] In the present invention, in step (3), part of the aqueous phase accounts for 4-8% of the total mass of the aqueous phase, preferably 5-7%; the mixing speed is 500-700 rpm, preferably 600 rpm; and the mixing time is 20-30 min, preferably 30 min.

[0075] In the present invention, in the step (4), the mixing speed is 500-700 rpm, the shear homogenization speed is 6000-8000 rpm, preferably 7000 rpm; the shear homogenization time is 20-30 min, preferably 30 min; the high-pressure homogenization pressure is 75-85 MPa, preferably 80 MPa.

[0076] In the present invention, in step (5), the mass ratio of colloidal microcrystalline cellulose to water is 0.8 to 1.2:9×10 4 ~1.1×10 5 , preferably 1.0: 1.0×10 5 ; The mixing temperature is 80-90°C, preferably 85°C; the mixing time is 30-40min, preferably 35min; the shear emulsification speed is 10000-11000rpm, preferably 10000rpm, and the shear emulsification time is 8-10min, preferably 9min.

[0077] In the present invention, in step (6), the mass ratio of water to sodium citrate is 200-300:0.4-0.8, preferably 220-280:0.5-0.7, and more preferably 240-260:0.6.

[0078] In the present invention, in the step (7), the mass ratio of water to fructose syrup is 550-650:8-10, preferably 600:9; the vitamin DK oral solution is filtered through a 200-300 mesh filter.

[0079] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0080] Example 1

[0081] Preparation of Vitamin DK Oral Solution:

[0082] Under light-proof conditions, weigh 200 g of medium-chain triglycerides, place in a 2000 mL beaker, add 25 g of butylated hydroxytoluene in a 70 ° C water bath and stir to dissolve, then add 1.0 g of vitamin D3 crystals in a 35 ° C water bath and stir to dissolve; then add 190 g of vitamin K2 and stir to dissolve; continue stirring in the water bath for 30 minutes as the oil phase for later use (total weight: 0.416 kg).

[0083] Weigh 3.5 kg of purified water, place in a 30L stainless steel barrel, add 3.5 kg of sodium starch octenyl succinate, stir at low speed in a 60°C water bath to dissolve (constant speed electric stirrer, the number of revolutions is about 200r), cool to room temperature and stand for defoaming for 5 hours (to fully defoam, the sodium starch octenyl succinate solution can be prepared one day in advance), then add 3.0 kg of glycerol, stir and mix evenly, as the water phase, for standby use (total weight: 10 kg)

[0084] Under stirring, take 0.5kg of water phase and slowly add it to the oil phase, and then stir at high speed for 20 minutes (constant speed electric stirrer, the number of revolutions is 500r) to obtain colostrum; transfer all the colostrum to the remaining water phase, stir at high speed for 30 minutes (constant speed electric stirrer, the number of revolutions is 600r), and then use SH digital display constant speed shear emulsification mixer, high speed (7000rpm) shear homogenization for 20 minutes (avoid overheating, add a cold water bath outside the container), and then homogenize once with a high-pressure homogenizer (80MPa) to obtain the embedding emulsion for use.

[0085] Take 1.0 kg of colloidal microcrystalline cellulose, add 100 L of purified water, heat to 85° C. and keep warm for 30 minutes. After cooling, use SH digital constant speed shear emulsifier mixer to shear and homogenize at high speed (10000 rpm) for 10 minutes to obtain a gel solution for standby use.

[0086] Weigh 250 kg of purified water and add it to the liquid preparation tank, add 0.6 kg of sodium citrate, 0.2 kg of sucralose, and 0.1 kg of sodium ascorbate, stir until dissolved, then add the above embedding emulsion and continue to stir evenly.

[0087] Add 600 kg of purified water and 10.0 kg of fructose syrup to the liquid preparation tank, then add the above concentrate, stir to make it evenly dispersed, turn on the stirring and vacuum pump, filter with a 1.0 micron polypropylene folded filter element, and then add glue and purified water to make the total volume to 800 L. Filter the above solution with a 300-mesh stainless steel filter to obtain a nanoemulsion, which is the vitamin DK oral solution.

[0088] Example 2

[0089] Preparation of Vitamin DK Oral Solution:

[0090] Under light-proof conditions, weigh 100 g of medium-chain triglycerides, place in a 2000 mL beaker, add 21 g of butylated hydroxytoluene in a 60 ° C water bath and stir to dissolve, then add 0.8 g of vitamin D3 crystals in a 35 ° C water bath and stir to dissolve; then add 180 g of vitamin K2 and stir to dissolve; continue stirring in the water bath for 30 minutes as the oil phase for later use (total weight: 0.3018 kg).

[0091] Weigh 3.0 kg of purified water, place in a 30L stainless steel barrel, add 3.0 kg of sodium starch octenyl succinate, stir at low speed in a 60°C water bath to dissolve (constant speed electric stirrer, the number of revolutions is about 200r), cool to room temperature and stand for defoaming for 4 hours (to fully defoam, the sodium starch octenyl succinate solution can be prepared one day in advance), then add 3.0 kg of glycerol, stir and mix evenly, as the water phase, for standby use (total weight: 9 kg)

[0092] Under stirring, take 0.4 kg of water phase and slowly add it to the oil phase, and then stir at high speed for 20 minutes (constant speed electric stirrer, the number of revolutions is 500r) to obtain colostrum; transfer all the colostrum to the remaining water phase, stir at high speed for 30 minutes (constant speed electric stirrer, the number of revolutions is 600r), and then use SH digital display constant speed shear emulsification mixer, high speed (7000rpm) shear homogenization for 20 minutes (avoid overheating, add a cold water bath outside the container), and then homogenize once with a high-pressure homogenizer (85MPa) to obtain the embedding emulsion for use.

[0093] Take 0.8 kg of colloidal microcrystalline cellulose, add 90 L of purified water, heat to 85° C. and keep warm for 30 minutes. After cooling, use SH digital constant speed shear emulsifier mixer to shear and homogenize at high speed (10000 rpm) for 10 minutes to obtain a gel solution for standby use.

[0094] Weigh 200 kg of purified water and add it to the liquid preparation tank, add 0.4 kg of sodium citrate, 0.1 kg of sucralose, and 0.2 kg of sodium ascorbate, stir until dissolved, then add the above embedding emulsion and continue to stir evenly.

[0095] Add 550 kg of purified water and 8.0 kg of fructose syrup to the liquid preparation tank, then add the above concentrate, stir to make it dispersed evenly, turn on the stirring and vacuum pump, filter with a 1.0 micron polypropylene folded filter element, add glue and purified water to make the total volume to 800 L. Filter the above solution with a 300-mesh stainless steel filter to obtain a nanoemulsion, which is the vitamin DK oral solution.

[0096] Example 3

[0097] Preparation of Vitamin DK Oral Solution:

[0098] Under light-proof conditions, weigh 300 g of medium-chain triglycerides, place in a 2000 mL beaker, add 30 g of butylated hydroxytoluene in a 60 ° C water bath and stir to dissolve, then add 0.7 g of vitamin D3 crystals in a 35 ° C water bath and stir to dissolve; then add 2200 g of vitamin K2 and stir to dissolve; continue stirring in the water bath for 30 minutes as the oil phase for later use (total weight: 0.5307 kg).

[0099] Weigh 4.0 kg of purified water, place in a 30L stainless steel barrel, add 3.0 kg of sodium starch octenyl succinate, stir at low speed in a 60°C water bath to dissolve (constant speed electric stirrer, the number of revolutions is about 200r), cool to room temperature and stand for defoaming for 6 hours (to fully defoam, the sodium starch octenyl succinate solution can be prepared one day in advance), then add 2.0 kg of glycerol, stir and mix evenly, as the aqueous phase, for standby use (total weight: 9 kg)

[0100] Under stirring, take 0.7kg of water phase and slowly add it to the oil phase, and then stir at high speed for 20 minutes (constant speed electric stirrer, the number of revolutions is 500r) to obtain colostrum; transfer all the colostrum to the remaining water phase, stir at high speed for 30 minutes (constant speed electric stirrer, the number of revolutions is 600r), and then use SH digital display constant speed shear emulsification mixer, high speed (7000rpm) shear homogenization for 20 minutes (avoid overheating, add a cold water bath outside the container), and then homogenize once with a high-pressure homogenizer (90MPa) to obtain the embedding emulsion for use.

[0101] Take 1.2 kg of colloidal microcrystalline cellulose, add 110 L of purified water, heat to 85° C. and keep warm for 30 minutes. After cooling, use SH digital constant speed shear emulsifier mixer to shear and homogenize at high speed (10000 rpm) for 10 minutes to obtain a gel solution for use.

[0102] Weigh 300 kg of purified water and add it to the liquid preparation tank, add 0.8 kg of sodium citrate, 0.2 kg of sucralose, and 0.2 kg of sodium ascorbate, stir until dissolved, then add the above embedding emulsion and continue to stir evenly.

[0103] Add 650 kg of purified water and 10.0 kg of fructose syrup to the liquid preparation tank, then add the above concentrate, stir to make it dispersed evenly, turn on the stirring and vacuum pump, filter with a 1.0 micron polypropylene folded filter element, and then add glue and purified water to make the total volume to 1000 L. Filter the above solution with a 200-mesh stainless steel filter to obtain a nanoemulsion, which is the vitamin DK oral solution.

[0104] The nanoemulsions obtained in Examples 1 to 3 were tested for performance:

[0105] Figure 1 This is a particle size detection report of the vitamin DK nanoemulsion prepared in Example 1 of the present invention. From the figure, it can be seen that the particle size is small and the particle size distribution is narrow. The particle size distribution range is 22 to 54 nm, and the average particle size is 36 nm.

[0106] Water solubility and stability test:

[0107] Water solubility: The nanoemulsions prepared in Examples 1 to 3 can be rapidly dissolved in water, and the solutions are clear, indicating that the vitamin DK nanoemulsions have good water solubility.

[0108] stability:

[0109] Physical stability: 30 mL of the vitamin DK nanoemulsion of Examples 1 to 3 were respectively placed in a centrifuge tube and centrifuged at 4000 r / min for 15 min. No stratification should be observed. The vitamin DK nanoemulsion prepared by the present invention was tested to have no stratification and the stability met the requirements.

[0110] Shaking test: 30 mL of each of the vitamin DK nanoemulsions of Examples 1 to 3 were taken, sealed in 50 mL test tubes, and shaken at 100 rpm in a 30°C constant temperature water bath oscillator. Samples were taken at 0 h, 12 h, 24 h, 48 h, and 72 h, and the centrifugal stability parameter Ke of the vitamin D nanoemulsion at each sampling time was measured. The results are shown in Table 1.

[0111] Table 1 Centrifugal stability parameters Ke of vitamin DK nanoemulsion

[0112] project Time / h 0h 12h 24h 48h 72h Example 1 Ke 0.325 0.332 0.341 0.343 0.348 Example 2 Ke 0.317 0.319 0.324 0.331 0.342 Example 3 Ke 0.321 0.329 0.336 0.340 0.347

[0113] Experiments have shown that continuous shaking has no effect on the Ke value of vitamin DK nanoemulsion.

[0114] Stability at different temperatures: 30 mL of each of the vitamin DK nanoemulsions of Examples 1 to 3 were taken, filled into sealed soda-lime glass bottles, and placed at 40°C, 60°C, and 70°C for 10 days, respectively. The particle size and distribution of the vitamin DK nanoemulsions were examined at 0 days, 5 days, and 10 days, respectively. The test results are shown in Table 2.

[0115] Table 2 Effect of different temperatures on the stability of vitamin DK nanoemulsion

[0116]

[0117] Experiments show that there is no significant change in the particle size of vitamin DK nanoemulsion at different temperatures. Since vitamin DK is a fat-soluble component, it is not easy to be stored for too long under high temperature conditions.

[0118] Accelerated test: The vitamin DK nanoemulsion was placed at 30°C for 6 months, and the physical properties of the vitamin DK nanoemulsion were examined at 0, 1, 2, 3, and 6 months. The test results are shown in Table 3.

[0119] Table 3 Effect of accelerated test on particle size of vitamin DK nanoemulsion

[0120]

[0121]

[0122] Accelerated tests have shown that under accelerated test conditions, the particle size of vitamin DK nanoemulsion has no significant change.

[0123] High temperature stability: The vitamin DK nanoemulsion was filled in a sealed soda-lime glass bottle and placed at 40°C, 60°C, and 70°C for 10 days, and the changes in the drug content in the vitamin DK nanoemulsion were observed at 0 days, 5 days, and 10 days. The test results are shown in Table 4.

[0124] Table 4 Content of vitamin DK nanoemulsion under different temperature and time conditions

[0125]

[0126] The test results show that when the vitamin DK nanoemulsion is placed under the above test conditions, the content of vitamin D and vitamin K does not change significantly during the storage period.

[0127] Accelerated testing

[0128] The vitamin DK nanoemulsion was placed at 37°C for 6 months, and the changes in the content of vitamin D3 and vitamin K2 at 0, 1, 2, 3, and 6 months were investigated. The test results are shown in Table 5.

[0129] Table 5 Drug content in the vitamin DK nanoemulsion after accelerated test at 37°C for 6 months

[0130]

[0131] The above experiments all show that there is no significant change in the physical and chemical indicators of vitamin DK nanoemulsion, and the vitamin DK nanoemulsion has good stability.

[0132] As can be seen from the above embodiments, the present invention provides a vitamin DK oral solution and a preparation method thereof. The present invention solves the quality and applicability of fat-soluble vitamin D and vitamin K in aqueous solution by exploring the use of nanoemulsion process technology. The technology of the present invention helps to improve the solubility, stability and bioavailability of drugs while reducing potential safety issues. Despite the challenges, oral liquid preparations still have broad market prospects due to their convenient, fast and easy-to-absorb characteristics. With the advancement of technology and the growth of market demand, it is expected that oral liquid preparations of fat-soluble vitamins will be further developed and optimized in the future.

[0133] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A vitamin DK oral solution, characterized in that: It is composed of the following components in parts by mass:

2. The method for preparing the vitamin DK oral solution according to claim 1, characterized in that: The following steps are involved: (1) medium chain triglyceride and butylated hydroxytoluene are mixed in a water bath, and then vitamin D3 and vitamin K2 are added in sequence to obtain an oil phase after mixing; (2) mixing water and sodium starch octenyl succinate in a water bath to obtain a sodium starch octenyl succinate solution, and adding glycerol to the sodium starch octenyl succinate solution and mixing to obtain an aqueous phase; (3) adding part of the water phase to the oil phase and mixing to obtain colostrum; (4) adding colostrum to the remaining aqueous phase, mixing, and then sequentially performing shear homogenization and high pressure homogenization to obtain an embedding emulsion; (5) adding water to the colloidal microcrystalline cellulose, mixing the mixture and then shearing and emulsifying the mixture to obtain a colloidal solution; (6) mixing water, sodium citrate, sucralose, sodium ascorbate and the embedding emulsion to obtain a concentrate; (7) Mix water, fructose syrup and concentrated solution, add gelatin solution after filtering, and add water to make up the volume to obtain vitamin DK oral solution.

3. The preparation method according to claim 2, characterized in that: In the step (1), the temperature of the water bath is 60-80°C, and the temperature for adding vitamin D3 is 30-50°C.

4. The preparation method according to claim 2 or 3, characterized in that: In the step (2), the mass ratio of water to sodium starch octenyl succinate is 3-4:3-4, the temperature of the water bath is 50-70° C., the mixing speed is 180-220 rpm, and the mixing time is 4-6 hours.

5. The preparation method according to claim 4, characterized in that: In the step (3), part of the aqueous phase accounts for 4 to 8% of the total mass of the aqueous phase, the mixing speed is 500 to 700 rpm, and the mixing time is 20 to 30 minutes.

6. The preparation method according to claim 2, 3 or 5, characterized in that: In the step (4), the mixing speed is 500-700 rpm, the shear homogenization speed is 6000-8000 rpm, the shear homogenization time is 20-30 min; and the pressure of the high-pressure homogenization is 75-85 MPa.

7. The preparation method according to claim 6, characterized in that: In the step (5), the mass ratio of colloidal microcrystalline cellulose to water is 0.8-1.2:9×10 4 ~1.1×10 5 ; The mixing temperature is 80-90° C., and the mixing time is 30-40 min. The rotation speed of the shear emulsification is 10000-11000 rpm, and the shear emulsification time is 8-10 min.

8. The preparation method according to claim 7, characterized in that: In the step (6), the mass ratio of water to sodium citrate is 200-300:0.4-0.

8.

9. The preparation method according to claim 7 or 8, characterized in that: In the step (7), the mass ratio of water to fructose syrup is 550-650:8-10; the vitamin DK oral liquid is filtered through a 200-300 mesh filter.

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