A fat-soluble vitamin embedding and its preparation method and application, a composite calcium carbonate / vitamin D3 preparation

Abstract

The application discloses a kind of fat-soluble vitamin inclusions, comprising: drug core and the zwitterionic membrane of drug core coating;Drug core is dissolved in oil phase material with fat-soluble vitamin;Zwitterionic membrane is obtained by crosslinking chitosan and sodium alginate.The application also discloses the preparation method of the above-mentioned fat-soluble vitamin inclusions, comprising the following steps: fat-soluble vitamin is dissolved in oil phase material to obtain oil phase;Take oil phase, sodium alginate aqueous solution and chitosan acetic acid aqueous solution to form W / O / W complex emulsion, so that sodium alginate is crosslinked with chitosan, then spray drying, obtain fat-soluble vitamin inclusions.The application also discloses the application of the above-mentioned fat-soluble vitamin inclusions in the preparation of calcium carbonate preparation.The application also discloses a kind of composite calcium carbonate / vitamin D3 preparation, and the raw materials include: calcium carbonate and the above-mentioned fat-soluble vitamin inclusions, wherein, fat-soluble vitamin is vitamin D3.The inclusions of the application are stable in quality, and can be uniformly mixed with calcium carbonate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a fat-soluble vitamin encapsulation compound, its preparation method and application, and a compound calcium carbonate / vitamin D3 formulation. Background Technology

[0002] Vitamins are essential nutrients for maintaining normal physiological functions in the human body, acting like "lubricant" and "catalyst" for bodily operations, helping various systems work efficiently. Different vitamins have specific functions, working together to protect health. Vitamins can be divided into two main categories: fat-soluble and water-soluble. Fat-soluble vitamins are those that are insoluble in water but soluble in fats and non-polar organic solvents (such as benzene, ether, and chloroform), including vitamins A, D, E, and K. Vitamin A (retinol): a protector of the eyes, maintaining retinal photosensitivity and preventing night blindness; it also protects the health of skin and mucous membranes, acting like a "protective shield" against external stimuli. Vitamin E: a cell protective shield, anti-oxidant that delays aging, and protects the vascular endothelium, acting like a "bulletproof vest" for cells. Vitamin K: a coagulation commander, helping to synthesize clotting factors, a key "coordinator" in the hemostasis process. Vitamin D3 (cholecalciferol) is mainly synthesized by the body itself. Human skin contains cholesterol, which is converted into vitamin D3 after exposure to sunlight. Vitamin D3 enhances the body's absorption of calcium and phosphorus, bringing plasma calcium and phosphorus levels to saturation, promoting growth and bone calcification, promoting healthy teeth, increasing phosphorus absorption through the intestinal wall, and increasing phosphorus reabsorption through the renal tubules. Fat-soluble vitamins are generally less stable and easily decompose under oxygen, high temperature, and light conditions. Maintaining the stability of these vitamins is a pressing issue that needs to be addressed.

[0003] Calcium is the most abundant mineral in the human body, a major component of bones, and a vital element for life. It is the most abundant inorganic element in the body, often referred to as the "element of life." However, calcium is easily lost from the body and needs to be replenished regularly. Calcium is essential for maintaining the normal function of the nervous, muscular, and skeletal systems, as well as cell membranes and capillary permeability. Calcium deficiency can lead to various diseases.

[0004] To promote calcium absorption, vitamin D3 is often used in conjunction with calcium supplements, such as calcium carbonate D3 tablets, calcium carbonate D3 chewable tablets, and children's calcium carbonate D3 granules. Calcium carbonate, as a calcium supplement, has a high calcium content and is one of the preferred sources of calcium for most people, while vitamin D3 is a hormone precursor that promotes the body's absorption of calcium and phosphorus.

[0005] Currently, in calcium carbonate D3 formulations, due to the small amount of vitamin D3 used, very low amounts of vitamin D3 often cannot be evenly mixed in high-dosage calcium carbonate formulations, resulting in large variations in vitamin D3 content within and between batches, thus affecting efficacy and quality uniformity. In addition, existing vitamin D3 also suffers from quality instability; furthermore, commercially available vitamin D3 powder particles are relatively large, which limits its suitability for specific formulation requirements. Therefore, preparing vitamin D3 encapsulation materials (vitamin D3 powder) with appropriate specifications and particle size and stable quality is an urgent problem to be solved. Summary of the Invention

[0006] Based on the technical problems existing in the background technology, the present invention proposes a fat-soluble vitamin encapsulation material, its preparation method and application, and a compound calcium carbonate / vitamin D3 preparation. The fat-soluble vitamin encapsulation material of the present invention has stable quality, can be uniformly mixed with calcium carbonate, and has a simple preparation method, which is suitable for large-scale industrial production.

[0007] This invention proposes a fat-soluble vitamin encapsulation material, comprising: a core and a zwitterion membrane encapsulating the core; the core is an oil phase substance containing dissolved fat-soluble vitamins; the zwitterion membrane is obtained by cross-linking chitosan and sodium alginate.

[0008] Preferably, the surface of the zwitterionic membrane is rough.

[0009] Preferably, the zwitterionic membrane is a monolayer membrane obtained by crosslinking chitosan and sodium alginate.

[0010] Preferably, the zwitterionic membrane is obtained by crosslinking chitosan and sodium alginate in a W / O / W double emulsion system.

[0011] Preferably, the zwitterionic membrane is formed by an oil phase substance, an aqueous solution of sodium alginate, and an aqueous solution of acetic acid in chitosan to create a W / O / W complex emulsion system, thereby crosslinking sodium alginate and chitosan.

[0012] The surface of the above-mentioned zwitterionic membrane is rough and has an uneven structure.

[0013] The particle size of the above-mentioned fat-soluble vitamin encapsulations is 70-200 mesh.

[0014] Preferably, the fat-soluble vitamins include at least one of vitamin D3, vitamin D2, vitamin D1, vitamin A, vitamin K, and vitamin E.

[0015] Preferably, the fat-soluble vitamin content in the fat-soluble vitamin encapsulation is 0.2-0.3 wt%.

[0016] Preferably, the weight ratio of the oil phase substance, chitosan, and sodium alginate is 120-200:380-480:0.5-2.

[0017] The oil phase substance mentioned above can be at least one of paraffin, medium-chain triglycerides, diacetylglycerol, triacetylglycerol and edible oil; more preferably, the oil phase substance is paraffin.

[0018] When the oil phase is a mixture of paraffin and edible oil, the paraffin content is ≥75wt%; the edible oil can be soybean oil, corn oil, hydrogenated soybean oil, peanut oil, rapeseed oil, cottonseed oil, sunflower seed oil, castor oil, etc.

[0019] The above-mentioned paraffin is a light liquid paraffin.

[0020] A fat-soluble antioxidant can also be added to the above-mentioned oil phase substance. The weight ratio of the oil phase substance to the fat-soluble antioxidant can be 120-200:2-6. The fat-soluble antioxidant can be one or more of the following: DL-α-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tert-butylhydroquinone (TBHQ), guaiac resin, etc.

[0021] The present invention also proposes a method for preparing the above-mentioned fat-soluble vitamin encapsulation, comprising the following steps: dissolving fat-soluble vitamins in an oil phase to obtain an oil phase; taking the oil phase, an aqueous solution of sodium alginate, and an aqueous solution of acetic acid in chitosan to form a W / O / W double emulsion, so that sodium alginate and chitosan are crosslinked, and then spray drying to obtain the fat-soluble vitamin encapsulation.

[0022] Preferably, the specific steps for forming a W / O / W double emulsion include: adding an aqueous solution of sodium alginate to the oil phase and emulsifying it to obtain a W / O primary emulsion; adding the primary emulsion dropwise to an aqueous solution of acetic acid containing chitosan while stirring to obtain a W / O / W double emulsion, thereby crosslinking sodium alginate with chitosan.

[0023] Preferably, after obtaining the W / O / W double emulsion, high-pressure homogenization is performed to crosslink sodium alginate with chitosan.

[0024] Preferably, the sodium alginate aqueous solution contains 0.5-2 wt% sodium alginate.

[0025] In the above-mentioned aqueous acetic acid solution of chitosan, the mass fraction of chitosan is 11-16 wt%.

[0026] The solvent for the above-mentioned chitosan aqueous solution of acetic acid is an aqueous solution of acetic acid with a pH of 4-5.

[0027] The above-mentioned acetic acid aqueous solution with pH=4-5 can be prepared by using a 0.5-2% volume fraction acetic acid aqueous solution and adjusting the pH to 4-5 with sodium hydroxide aqueous solution.

[0028] The above-mentioned W / O primary emulsion is a micro / nano emulsion; in the above-mentioned W / O primary emulsion, the droplet size is ≤5μm.

[0029] The stirring speed for the above-mentioned drip-addition and stirring is 400-600 rpm.

[0030] The temperatures of the oil phase, sodium alginate aqueous solution, and chitosan acetic acid aqueous solution were all 60-90℃.

[0031] The inlet air temperature for the above spray drying is 40-60℃; the peristaltic pump speed for spray drying is 100-200 rpm.

[0032] The present invention also discloses the application of the above-mentioned fat-soluble vitamin encapsulation material in the preparation of calcium carbonate preparations.

[0033] The present invention also discloses a compound calcium carbonate / vitamin D3 preparation, the raw materials of which include: calcium carbonate and the above-mentioned fat-soluble vitamin encapsulation, wherein the fat-soluble vitamin is vitamin D3.

[0034] The weight ratio of the calcium carbonate and vitamin D3 encapsulation material can be 100-800:1.

[0035] The raw materials for the aforementioned compound calcium carbonate / vitamin D3 preparation also include other pharmaceutical excipients.

[0036] The above-mentioned pharmaceutical excipients may include: microcrystalline cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, povidone K30, sodium lauryl sulfate, magnesium stearate, sorbitol, compressible sugar, mannitol, orange-flavored granules, sucralose, sunset yellow, stearic acid, sodium citrate, silicon dioxide, etc.

[0037] The aforementioned compound calcium carbonate / vitamin D3 preparation can be in the form of tablets, chewable tablets, granules, etc. The tablets can be coated tablets, coated using film-coating premixes, etc. The compound calcium carbonate / vitamin D3 preparation can be prepared using conventional methods in the art.

[0038] The specific formula of the above-mentioned compound calcium carbonate / vitamin D3 coated tablets may include, by weight of each raw material: 1250-1750 parts calcium carbonate, 2.5 parts vitamin D3 encapsulation material (i.e., vitamin D3 powder), 35-50 parts microcrystalline cellulose, 60-90 parts crospovidone, 40-70 parts crospovidone sodium carboxymethyl cellulose, 65-75 parts povidone K30, 7-9 parts sodium dodecyl sulfate, 5-10 parts magnesium stearate, and 50-60 parts film coating premix.

[0039] The specific formula of the above-mentioned compound calcium carbonate / vitamin D3 chewable tablets may include, by weight of each ingredient: 750 parts calcium carbonate, 1.25-5 parts vitamin D3 encapsulation (i.e., vitamin D3 powder), 100-800 parts sorbitol, 10-100 parts compressible sugar, 100-800 parts mannitol, 10-30 parts orange-flavored granules, 1-3 parts sucralose, 1-5 parts sunset yellow, 10-50 parts stearic acid, and 10-50 parts magnesium stearate.

[0040] The specific formula for compound calcium carbonate / vitamin D3 granules, by weight of each raw material, may include: 1250 parts calcium carbonate, 2-5 parts vitamin D3 encapsulation (i.e., vitamin D3 powder), 50-400 parts microcrystalline cellulose, 50-400 parts sorbitol, 10-30 parts orange-flavored granules, 1-3 parts sucralose, 2-15 parts sodium citrate, and 2-10 parts silicon dioxide.

[0041] The above-mentioned compound calcium carbonate / vitamin D3 preparation can be used as a calcium supplement for children, pregnant and lactating women, menopausal women, the elderly, etc., and can help prevent and treat osteoporosis.

[0042] This invention dissolves fat-soluble vitamins in an oil phase to obtain an oil phase, and then uses the oil phase, an aqueous solution of sodium alginate, and an aqueous solution of chitosan in acetic acid to form a W / O / W double emulsion system. This allows sodium alginate and chitosan to crosslink, resulting in a fat-soluble vitamin encapsulation. The fat-soluble vitamins dissolve in the oil phase to form a core, which provides a relatively stable dissolution environment for the fat-soluble vitamins, reducing their contact with the external environment and thus improving their stability. Furthermore, the light liquid paraffin has good chemical stability and low volatility, which can further enhance the stability of the fat-soluble vitamins.

[0043] Furthermore, in the W / O / W double emulsion system, sodium alginate aqueous solution serves as the inner aqueous phase, and chitosan acetic acid aqueous solution serves as the outer aqueous phase. After stirring and high-pressure homogenization, sodium alginate droplets and chitosan solution diffuse and attract each other. At the moment of contact, cross-linking occurs at the oil-water interface through electrostatic adsorption, forming a dense, robust, and network-structured zwitterionic membrane that encapsulates the drug core. On the one hand, the zwitterionic membrane can form a physical isolation layer, reducing the direct contact and mutual attraction between fat-soluble vitamin encapsulation particles, allowing the fat-soluble vitamin encapsulation particles to exist in a more dispersed state and avoiding self-aggregation of the fat-soluble vitamin encapsulation particles. Regarding the interaction between the fat-soluble vitamin encapsulation particles and calcium carbonate particles... During mixing, in a calcium carbonate environment, the zwitterionic membrane carries a slight negative charge, which reduces the electrostatic repulsion between the fat-soluble vitamin encapsulation and calcium carbonate, increases the surface energy matching degree between the two, and thus significantly improves the mixing uniformity. On the other hand, during cross-linking, chitosan forms microcrystalline regions in the acidic external aqueous phase, and the sodium alginate gel network intersperses among them, forming an uneven structure, which makes the surface of the zwitterionic membrane rough. When it is mixed with calcium carbonate particles, it can effectively increase the friction and contact area between the zwitterionic membrane and the calcium carbonate particles. Moreover, the rough surface also helps the fat-soluble vitamin encapsulation particles to better adhere to the surface of calcium carbonate particles, promoting the uniform mixing of the two and improving the mixing uniformity.

[0044] In addition, the zwitterionic membrane has a certain degree of hardness, which can resist pressure and prevent membrane rupture. During the tableting process, the fat-soluble vitamin encapsulation particles will not break due to high tableting pressure, thus preventing the degradation and reduction of fat-soluble vitamin content.

[0045] Furthermore, fat-soluble vitamin encapsulations can be obtained using ordinary spray drying without the need for additional excipients such as starch, which improves production efficiency and reduces dust pollution and the risk of powder explosion during the production process.

[0046] The preparation process of this invention is simple and suitable for large-scale industrial production. The resulting fat-soluble vitamin encapsulation material has stable quality and can be uniformly mixed with calcium carbonate. Attached Figure Description

[0047] Figure 1-3 The images shown are, in order, microscope images of the vitamin D3 embeddings prepared in Examples 5, 10, and 11. Detailed Implementation

[0048] The technical solution of the present invention will be described in detail below through specific embodiments. However, it should be clearly stated that these embodiments are only for illustrative purposes and are not intended to limit the scope of the present invention.

[0049] Examples 1-5

[0050] Vitamin D3 encapsulations were prepared according to the formulas in Table 1.

[0051]

[0052] The preparation methods for the above vitamin D3 embeddings are the same, including the following steps:

[0053] Place the oil phase material in a beaker, place it on a magnetic stirrer, heat and stir at 60-90℃, then add DL-α-tocopherol and vitamin D3 to dissolve them, and obtain the oil phase;

[0054] Add water to a beaker, heat in a water bath at 60-90℃, add sodium alginate, and stir for more than 30 minutes until the sodium alginate is completely swollen to obtain an aqueous solution of sodium alginate, which is referred to as the inner aqueous phase.

[0055] Chitosan was added to a 1% acetic acid aqueous solution (pH adjusted to 5.0 with sodium hydroxide aqueous solution), and heated and stirred at 60-90℃ to obtain an acetic acid aqueous solution of chitosan, which was denoted as the external aqueous phase.

[0056] The aqueous phase is added to the oil phase while stirring at 1000-1500 rpm for 1-2 hours. Then, it is homogenized under high pressure to obtain a W / O primary emulsion, which is a micro / nano emulsion with a droplet size ≤5μm.

[0057] Then, the W / O colostrum was added dropwise to the external aqueous phase while stirring at a low speed of 500 rpm to form a W / O / W double emulsion. After high-pressure homogenization, sodium alginate and chitosan formed an amphoteric membrane.

[0058] W / O / W double emulsions were subjected to low-temperature spray drying with an inlet air temperature of 40-60℃ and a peristaltic pump speed of 100-200rpm. The mixture was then subjected to high-speed centrifugal granulation to obtain vitamin D3 encapsulated material with a particle size of 70-200 mesh. The yield of each group was not less than 85%.

[0059] The stability of the vitamin D3 encapsulated materials prepared in Examples 1-5 was examined and compared with that of vitamin D3 raw material. The results are shown in Table 2.

[0060]

[0061] As shown in Table 2, under high temperature of 60℃, the content of vitamin D3 raw material degraded by 57.24% after 10 days and by 95.43% after 30 days, indicating that vitamin D3 is sensitive to high temperature and extremely unstable. Preparing vitamin D3 into an encapsulation material can greatly improve its stability. Furthermore, the stability of Examples 4-5 is significantly better than that of Examples 1-3, indicating that the addition of light liquid paraffin can significantly improve the stability of vitamin D3 at high temperature of 60℃.

[0062] Examples 6-9

[0063] Vitamin D3 embeddings were prepared according to the formulas in Table 3, and the preparation methods were the same as in Example 5.

[0064]

[0065] The stability of the vitamin D3 encapsulations prepared in Examples 6-9 was examined and compared with the results of Example 5. The results are shown in Table 4.

[0066]

[0067] As can be seen from Tables 2 and 4, the encapsulation efficiency and stability of Examples 5 and 7-9 are much better than those of Example 6, indicating that the concentration of the sodium alginate aqueous solution in the inner aqueous phase affects the encapsulation efficiency and stability of vitamin D3; vitamin D3 encapsulation materials prepared with a sodium alginate aqueous solution mass fraction in the range of 0.5-2wt% have better encapsulation efficiency and stability.

[0068] Examples 10-11

[0069] Vitamin D3 embeddings were prepared according to the formulas in Table 5, and the preparation methods were the same as in Example 5.

[0070]

[0071] The stability of the vitamin D3 embeddings prepared in Examples 10-11 was examined and compared with the results of Example 5. The results are shown in Table 6. Figure 1-3 As shown.

[0072] Figure 1-3 The images shown are, in order, microscope images of the vitamin D3 embeddings prepared in Examples 5, 10, and 11.

[0073]

[0074] From Table 6 and Figure 1-3 It can be seen that the encapsulation efficiency and stability of Examples 5 and 10 are much better than those of Example 11, and the particle size of the encapsulated materials obtained in Examples 5 and 10 is also much smaller than that in Example 11. This indicates that the pH value of the acetic acid aqueous solution affects the encapsulation efficiency, stability, and particle size of the vitamin D3 encapsulated materials. Using an acetic acid aqueous solution with pH=4.0-5.0 as the solvent of the external aqueous phase, the vitamin D3 encapsulated materials prepared have high encapsulation efficiency and high stability, and the particle size is suitable for formulation development. In contrast, the vitamin D3 encapsulated materials prepared with an acetic acid aqueous solution with pH=6.0 have low encapsulation efficiency and larger particles.

[0075] Examples 12-15

[0076] Vitamin D3 encapsulations were prepared according to the formulas in Table 7, and the preparation methods were the same as in Example 5.

[0077]

[0078] As shown in Table 7, the encapsulation rates of Examples 5, 12-13, and 15 are better than that of Example 14. However, the particle size of the encapsulated material obtained in Example 12 is much larger than that in Example 5, indicating that the concentration of the chitosan-acetic acid aqueous solution affects the encapsulation rate and particle size of the vitamin D3 encapsulated material. Using a chitosan-acetic acid aqueous solution with a mass fraction of 11-16 wt% as the external aqueous phase, the vitamin D3 encapsulated material prepared has a high encapsulation rate and the particle size is suitable for formulation development.

[0079] Comparative Example 1

[0080] A vitamin D3 embedding compound, the preparation method of which includes the following steps:

[0081] Take 200g of light liquid paraffin, heat and stir at 60-90℃, then add 2g of DL-α-tocopherol and 1.5g of vitamin D3 to dissolve, and obtain the oil phase; dissolve 380g of sodium alginate in water at 60-90℃ to obtain a sodium alginate aqueous solution with a mass fraction of 0.9wt%; add the oil phase to the sodium alginate aqueous solution and homogenize and emulsify under high pressure to obtain an emulsion; then perform low-temperature spray drying, with an inlet air temperature of 40-60℃, a peristaltic pump speed of 100-200rpm, and high-speed centrifugal granulation to obtain vitamin D3 encapsulation.

[0082] Comparative Example 2

[0083] A vitamin D3 encapsulation compound is prepared by the following steps: 200g of light liquid paraffin is heated and stirred at 60-90℃, then 2g of DL-α-tocopherol and 1.5g of vitamin D3 are added and dissolved to obtain an oil phase; 380g of chitosan is added to 3000g of a 1% acetic acid aqueous solution with pH=5.0 (pH adjusted with sodium hydroxide aqueous solution), and heated and stirred at 60-90℃ to obtain an acetic acid aqueous solution of chitosan; the oil phase is added to the acetic acid aqueous solution of chitosan and homogenized under high pressure to obtain an emulsion; then spray drying is performed with an inlet air temperature of 40-60℃, a peristaltic pump speed of 100-200rpm, and high-speed centrifugal granulation to obtain the vitamin D3 encapsulation compound.

[0084] Comparative Example 3

[0085] A vitamin D3 embedding compound is prepared by the following steps: 200g of light liquid paraffin is heated and stirred at 60-90℃, and then 2g of DL-α-tocopherol and 1.5g of vitamin D3 are added and dissolved to obtain an oil phase;

[0086] Dissolve 0.9g of sodium alginate in 100g of water at 60-90℃ to obtain an aqueous solution of sodium alginate; add 380g of chitosan to 3000g of 1% acetic acid aqueous solution with pH=5.0 (adjust pH with sodium hydroxide aqueous solution), heat and stir at 60-90℃ to obtain an acetic acid aqueous solution of chitosan.

[0087] Sodium alginate aqueous solution and chitosan acetic acid aqueous solution were mixed and then added to the oil phase. The mixture was homogenized under high pressure to obtain an emulsion. Then, it was spray dried with an inlet air temperature of 40-60℃ and a peristaltic pump speed of 100-200rpm. The mixture was then centrifuged at high speed to obtain vitamin D3 encapsulation.

[0088] Comparative Example 4

[0089] A vitamin D3 embedding compound is prepared by means of the following steps: replacing sodium alginate with gum arabic, and otherwise following the same procedure as in Example 5, to obtain the vitamin D3 embedding compound.

[0090] Comparative Example 5

[0091] A vitamin D3 embedding compound is prepared by means of the following steps: replacing chitosan with gum arabic, replacing the 1% acetic acid aqueous solution with pH=5.0 with water, and so on as in Example 5, to obtain the vitamin D3 embedding compound.

[0092] The stability of the vitamin D3 encapsulated materials prepared in Comparative Examples 1-5 was examined and compared with that in Example 5. The results are shown in Table 8.

[0093]

[0094] As can be seen from Table 8, the content, encapsulation rate and stability of Comparative Examples 1-5 are much lower than those of Example 5.

[0095] Examples 16-24

[0096] Using the vitamin D3 encapsulations obtained in Examples 1, 5, and 6, compound calcium carbonate / vitamin D3 formulations (including tablets, chewable tablets, and granules) were prepared, and their stability was investigated. The formulations of the tablets, chewable tablets, and granules are shown in Tables 9-11.

[0097]

[0098] The preparation method of the above-mentioned compound calcium carbonate / vitamin D3 tablets includes the following steps:

[0099] Calcium carbonate and partially croscarmellose sodium were mixed through a 24-mesh sieve to obtain a mixture, wherein the amount of croscarmellose sodium was 0.5 times its total weight. Povidone K30 was dissolved in purified water at 40-60℃ to obtain a binder. The mixture was added to a fluidized bed, and the binder was added for granulation. The fluidized bed inlet air temperature was 60-80℃, the atomization pressure was 15-25psi, and the peristaltic pump speed was 25-35rpm, maintaining the material temperature at 26-32℃. After granulation, the mixture was dried until the moisture content was ≤2%, and then passed through a 40-mesh sieve to obtain dry calcium carbonate granules. The dry calcium carbonate granules, croscarmellose, microcrystalline cellulose, and the remaining croscarmellose sodium were mixed to obtain mixed granules I.

[0100] Vitamin D3 encapsulation and mixed particles I were added in equal proportions of 1:1 to 1:5 and mixed at a mixing frequency of 8-11 Hz for 10-15 minutes to obtain mixed particles II; finally, sodium dodecyl sulfate was added and mixed for 3 minutes to obtain mixed particles III.

[0101] The mixed granules III are compressed to obtain tablet cores with a hardness between 100-300N; then the film coating premix is ​​dispersed in 50-70% ethanol-water to obtain a coating solution, which is used to coat the tablet cores to obtain compound calcium carbonate / vitamin D3 tablets.

[0102]

[0103] The preparation method of the above-mentioned compound calcium carbonate / vitamin D3 chewable tablets includes the following steps:

[0104] According to the prescription, calcium carbonate, sorbitol, and mannitol are mixed in a wet granulator at a mixing speed of 200-400 rpm and a shearing speed of 800-1200 rpm for 2-5 minutes. Using a Sunset Yellow and K30 aqueous solution at 40-60℃ as a binder, granulation is performed at a mixing speed of 200-400 rpm and a shearing speed of 800-1200 rpm for 2-5 minutes. Granulation is then carried out using a 24-mesh sieve, followed by drying at 40-60℃ for at least 30 minutes, granulation using a 24-mesh sieve, and further drying until the moisture content is less than 2%, yielding mixed granules I.

[0105] Mix granules I with sucralose, compressible sugar, and orange-flavored granules at a mixing frequency of 10-15 Hz for 10-15 min to obtain mixed granules II;

[0106] The vitamin D3 embedding material and mixed particles II were added in equal proportions of 1:1 to 1:5 and mixed at a mixing frequency of 10-15 Hz for 10-15 min to obtain mixed particles III.

[0107] Mixed particles III are mixed with stearic acid and magnesium stearate at a mixing frequency of 10-15 Hz for 3-5 minutes to obtain total mixed particles; the total mixed particles are compressed into tablets to obtain compound calcium carbonate / vitamin D3 chewable tablets with a hardness controlled at 100-150 N.

[0108]

[0109] The preparation method of the above-mentioned compound calcium carbonate / vitamin D3 granules includes the following steps:

[0110] According to the prescription, calcium carbonate, microcrystalline cellulose, and sorbitol are mixed in a wet granulator at a mixing speed of 100-300 rpm and a shearing speed of 400-800 rpm for 2-5 minutes. Granulation is then carried out using a 40-60℃ aqueous solution as a binder at a mixing speed of 100-300 rpm and a shearing speed of 400-800 rpm for 3-5 minutes. After granulation through a 20-mesh sieve, the granules are dried at 40-60℃ for at least 30 minutes, sieved through a 24-mesh sieve, and dried further until the moisture content is less than 2%, yielding mixed granules I.

[0111] Mixed granules I with orange-flavored granules, sucralose and sodium citrate at a mixing frequency of 10-15 Hz for 10-15 min to obtain mixed granules II;

[0112] The vitamin D3 embedding material and mixed granules II were added in equal proportions of 1:1 to 1:5 and mixed at a mixing frequency of 10-15 Hz for 10-15 min to obtain mixed granules III.

[0113] Mixed particles III are mixed with silica at a frequency of 10-15 Hz for 3 minutes; then bagged according to theoretical weight.

[0114] The stability of the compound calcium carbonate / vitamin D3 preparations in each group was investigated, and the results are shown in Table 12.

[0115]

[0116] As can be seen from Table 12, the stability of vitamin D3 in the formulation is closely related to the stability of the vitamin D3 encapsulation material; the formulation prepared using vitamin D3 encapsulation materials with good stability also has good stability.

[0117] Example 25

[0118] The particle size range of the vitamin D3 encapsulation in Example 5 and commercially available vitamin D3 powder was investigated, and the results are shown in Table 13.

[0119]

[0120] Take the mixed particles I from the preparation process of the above-mentioned compound calcium carbonate / vitamin D3 tablets, and examine the mixing uniformity of them with the vitamin D3 encapsulation material of Example 5 and the commercially available vitamin D3 powder. The results are shown in Table 14.

[0121]

[0122] As shown in Table 14, the vitamin D3 embedding material and mixed particles I in Example 5, added in equal proportions from 1:1 to 1:5, can all meet the mixing uniformity requirements of vitamin D3 in calcium carbonate preparations. Compared to commercially available vitamin D3 powder, which is limited to equal-volume addition, this method improves mixing uniformity and greatly increases production efficiency. Furthermore, commercially available vitamin D3 powder is not sieved, resulting in a larger RSD (Restricted Scaling Degree) of vitamin D3 content after mixing. While sieving through a 70-mesh sieve significantly improves mixing uniformity, it is still inferior to the vitamin D3 embedding material prepared in Example 5. Moreover, sieving commercially available vitamin D3 powder greatly reduces its utilization rate. Compared to commercially available vitamin D3 powder, the vitamin D3 embedding material prepared by this invention has more uniform particle size, better compatibility with the preparation, higher utilization rate, and significantly reduced costs. Moreover, the vitamin D3 embedding material prepared by this invention, after mixing with calcium carbonate particles, is less prone to stratification during storage, thus ensuring uniform and stable product quality.

[0123] Example 26

[0124] The vitamin D3 encapsulation material from Example 5 and commercially available vitamin D3 powder were used to prepare composite calcium carbonate / vitamin D3 tablets according to the above method. The stability of the formulation under different core hardness was investigated and compared with commercially available calcium carbonate / D3 tablets. The results are shown in Table 15.

[0125]

[0126] Table 15 shows that during the tableting process, the effect of different core hardness on the stability of vitamin D3 in calcium carbonate / D3 tablets was investigated. The stability of calcium carbonate / D3 tablets with different hardnesses prepared using commercially available vitamin D3 powder was compared with that of commercially available calcium carbonate / D3 tablets with a large market share. It was found that the zwitterionic membrane formed on the surface of the vitamin D3 encapsulation prepared using this invention has a certain compressive strength, preventing the vitamin D3 particles from rupturing due to high tableting pressure, thus avoiding degradation of the content during storage.

[0127] Example 27

[0128] By replacing vitamin D3 with vitamin D (including vitamin D1 and vitamin D2), vitamin A, vitamin E, and vitamin K, the respective encapsulated compounds can be prepared according to the formulation and preparation method of Example 5, with encapsulation rates of 99.78%, 99.65%, 99.71%, and 98.42%, respectively.

[0129] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A fat-soluble vitamin embedment, characterized in that, The application relates to a fat-soluble vitamin embedding material, which comprises: a core and a zwitterionic membrane covering the core; the core is an oil-phase substance in which a fat-soluble vitamin is dissolved; the zwitterionic membrane is obtained by cross-linking chitosan and sodium alginate; the zwitterionic membrane is formed by an oil-phase substance, an aqueous sodium alginate solution and an aqueous chitosan-acetic acid solution to form a W / O / W multiple emulsion system, so that the sodium alginate is cross-linked with the chitosan; in the W / O / W multiple emulsion system, the aqueous sodium alginate solution serves as an inner water phase and the aqueous chitosan-acetic acid solution serves as an outer water phase; the oil-phase substance is one of liquid paraffin and a mixture of liquid paraffin and edible oil; the weight ratio of the oil-phase substance, the chitosan and the sodium alginate is 120-200:380-480:0.5-2; the mass fraction of the sodium alginate in the aqueous sodium alginate solution is 0.5-2 wt%; the mass fraction of the chitosan in the aqueous chitosan-acetic acid solution is 11-16 wt%; the solvent of the aqueous chitosan-acetic acid solution is an aqueous acetic acid solution with a pH value of 4-5; the fat-soluble vitamin includes at least one of vitamin D3, vitamin D2, vitamin D1, vitamin A, vitamin K and vitamin E; the content of the fat-soluble vitamin in the fat-soluble vitamin embedding material is 0.2-0.3 wt%. The application further relates to a preparation method of the fat-soluble vitamin embedding material, which comprises the following steps: dissolving the fat-soluble vitamin in the oil-phase substance to obtain an oil phase; forming a W / O / W multiple emulsion by adding the oil phase, the aqueous sodium alginate solution and the aqueous chitosan-acetic acid solution, so that the sodium alginate is cross-linked with the chitosan, and then spray drying to obtain the fat-soluble vitamin embedding material. The specific steps for forming the W / O / W multiple emulsion include: adding the aqueous sodium alginate solution into the oil phase to emulsify and obtain a W / O primary emulsion; adding the primary emulsion into the aqueous chitosan-acetic acid solution drop by drop while stirring to obtain the W / O / W multiple emulsion, so that the sodium alginate is cross-linked with the chitosan.

6. Use of the fat-soluble vitamin embedding material according to any one of claims 1-3 in the preparation of a calcium carbonate preparation. The raw materials of the calcium carbonate preparation include: calcium carbonate and the fat-soluble vitamin embedding material according to any one of claims 1-3, wherein the fat-soluble vitamin is vitamin D3. ​ ​ ​ ​ 2. The fat-soluble vitamin embedment of claim 1, wherein, ​ 3. The fat-soluble vitamin embedment of claim 1, wherein, ​ 4. A process for the preparation of a fat-soluble vitamin embedding according to any one of claims 1 to 3, characterized in that, ​ 5. The method of claim 4, wherein the fat-soluble vitamin inclusion is prepared by, ​ ​ 7. A composite calcium carbonate / vitamin D3 preparation, characterized in that, ​

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