Fat-soluble vitamin formulation intermediate and preparation method therefor

Abstract

A fat-soluble vitamin formulation intermediate and a preparation method therefor. The fat-soluble vitamin formulation intermediate comprises, in parts by weight, 0.001-5 parts of a fat-soluble vitamin, 90-99.995 parts of a cyclodextrin derivative, and 0.004-5 parts of an antioxidant. Using the fat-soluble vitamin, the antioxidant, and the cyclodextrin derivative to form an inclusion complex, the fat-soluble vitamin formulation intermediate with simple components, a simple and convenient process, suitability for industrial production, and excellent stability is obtained.

Description

A fat-soluble vitamin preparation intermediate and its preparation method Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a fat-soluble vitamin preparation intermediate and a preparation method thereof. Background Art

[0002] Fat-soluble vitamins are a class of substances that play a significant role in maintaining normal human function. After entering the gastrointestinal tract, they dissolve in lipid particles and are absorbed in the intestines through the emulsification of bile. They then enter various organs through the lymphatic system, where they are mostly stored in adipose tissue, with only a small amount excreted. Fat-soluble vitamins primarily include vitamin A, vitamin D, vitamin E, vitamin K, and their derivatives. They are soluble in oils and fats, insoluble in water, and have relatively poor stability.

[0003] Generally speaking, the daily vitamin requirement of the human body can be supplemented from a normal diet, and the required amount is very small and is often calculated in milligrams (mg) or micrograms (μg); however, for some special groups, such as infants, the elderly, and people with food preferences, the intake of fat-soluble vitamins is often insufficient. If additional supplements are not taken, symptoms of vitamin deficiency may occur. Medicines, health foods, and other foods with added vitamins as nutritional enhancers can be selected as additional vitamin supplements.

[0004] Among the various commercially available products, the addition forms of fat-soluble vitamins are mainly divided into two categories: raw materials and preparation intermediates. Adding materials in the form of raw materials often has stability problems, resulting in a shorter shelf life of the finished product, or excessive addition is used to ensure the content limit, which brings production costs and safety issues of excessive content. Adding materials in the form of preparation intermediates can not only improve the stability of the finished product, extend the shelf life, but also simplify production operations. However, various vitamin preparation intermediates currently available on the market, such as fat-soluble vitamin granules, are mostly made in the form of microcapsules, contain multiple ingredients, and have a complex preparation process. In addition, although their stability is better than that of the corresponding fat-soluble vitamin raw materials, there is still a decrease in content during long-term storage and application.

[0005] Patent CN113730359A discloses a fat-soluble vitamin solid particle and its preparation method and application. The fat-soluble vitamin solid particle includes a fat-soluble vitamin, an emulsifier, an antioxidant, a filler and an optional oil phase solvent. It is believed that mixing the components in a molten or liquid form improves the content uniformity of the product and obtains fat-soluble vitamin solid particles with low content specifications. The particle size of the fat-soluble vitamin solid particles is reduced by the spray drying method, reducing the risk of content uniformity failure in the mixing process. In addition, the fat-soluble vitamin solid particles obtained by using two antioxidants with different oxidation potentials have a relative content after storage that is significantly better than commercially available products and comparative products. However, the fat-soluble vitamin solid particles disclosed in this patent contain multiple ingredients, the preparation process is relatively complex, and the stability needs to be further improved.

[0006] Patent CN114668726A discloses a vitamin D3 mixed powder and a preparation method thereof, comprising an aqueous phase component and an oil phase component, wherein the aqueous phase component comprises sodium starch octenylsuccinate, sucrose and sodium ascorbate, and the oil phase component comprises tocopherol, medium-chain triglycerides and vitamin D3. It is believed that when preparing the vitamin D3 mixed powder, spray drying is carried out under the protection of a nitrogen closed system during the process of converting the vitamin D3 emulsion into a powder, which can fully protect the vitamin D3 in the vitamin D3 mixed powder and effectively avoid the loss of vitamin D3, so that the vitamin D3 content in the finally prepared vitamin D3 mixed powder can still be basically consistent with the content in the initial ratio, fully ensuring the accuracy of the vitamin D3 content. However, the vitamin D3 mixed powder disclosed in this patent contains multiple ingredients, the preparation process is relatively complicated, and the stability needs to be further improved.

[0007] Patent CN115581303A discloses a vitamin solid, a preparation method, and its application, comprising vitamins, oils, antioxidants, encapsulating agents, emulsifiers, and nucleating agents. It is believed that spray drying an emulsion of vitamins and their derivatives under the action of a nucleating agent produces a stable vitamin core-shell structure, thereby solving the problem of vitamin content loss during preparation and storage. However, the vitamin solid disclosed in this patent contains multiple ingredients, the preparation process is relatively complex, and the stability needs to be further improved.

[0008] Patent GB2037773B discloses a process for preparing stabilized vitamin D and its composition, comprising forming a homogeneous solution of the vitamin D to be complexed and cyclodextrin in an ethanol-water solution at a certain temperature, and separating the desired inclusion complex from the solution by cooling and / or evaporating the solvent. This preparation method requires heating the ethanol solution and uses a large amount of ethanol, making the operation complex. This method, on the one hand, poses a high production safety risk, and on the other hand, the product produced also poses a significant application safety risk due to the presence of residual ethanol.

[0009] Patent CN1110275A discloses an inclusion complex of vitamin D and hydroxypropyl-β-cyclodextrin. The preparation method of the inclusion complex includes multiple steps such as ethanol dissolution, filtration, reduced pressure concentration, nitrogen drying, ice water dissolution, filtration, and freeze drying. The process is relatively cumbersome. The entire preparation process must be carried out in an oxygen-free and light-proof environment, and may cause vitamin D degradation, making it difficult to carry out large-scale production.

[0010] Therefore, this field urgently needs a vitamin preparation intermediate with simple ingredients, simple process, suitability for industrial production and excellent stability. Summary of the Invention

[0011] To solve the above problems, the present invention provides a new vitamin preparation intermediate, which uses fat-soluble vitamins, antioxidants and cyclodextrin derivatives to form an inclusion compound, thereby obtaining a fat-soluble vitamin preparation intermediate with simple ingredients, simple process, suitability for industrial production and excellent stability.

[0012] In one aspect, the present invention provides a fat-soluble vitamin preparation intermediate, which comprises, by weight, 0.001-5 parts of fat-soluble vitamins, 90-99.995 parts of cyclodextrin derivatives, and 0.004-5 parts of antioxidants.

[0013] The cyclodextrin derivative is a cyclodextrin derivative with good water solubility, including β-cyclodextrin.

[0014] As can be understood, cyclodextrin derivatives are high-molecular substances with a conical annular cavity in their molecular structure. The cavity is hydrophilic on the outside and hydrophobic on the inside. This cavity can trap fat-soluble vitamin molecules within the cyclodextrin derivative cavity to form inclusion complexes. Furthermore, excessive cyclodextrin derivative molecules aggregate to form a wall-like material, encapsulating the fat-soluble vitamin molecules between the cyclodextrin derivative molecules, isolating them from external contact and oxidative degradation, thereby improving the stability of the fat-soluble vitamins. In particular, the addition of antioxidants and fat-soluble vitamins to form inclusion complexes with cyclodextrin can further enhance the stability of fat-soluble vitamins.

[0015] The weight portion of the soluble vitamin is 0.001-5 parts, for example, it can be 0.001 parts, 0.03 parts, 0.4 parts, 1 parts, 2 parts, 3 parts, 4 parts or 5 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0016] The weight proportion of the cyclodextrin derivative is 90-99.995 parts, for example, it can be 90 parts, 91 parts, 92 parts, 93 parts, 94 parts, 96 parts, 97 parts, or 99.995 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0017] The weight portion of the antioxidant is 0.004-5 parts, for example, it can be 0.004 parts, 0.03 parts, 0.4 parts, 1 parts, 2 parts, 3 parts or 5 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0018] In some embodiments, the fat-soluble vitamins include one or more of vitamin A and its derivatives, vitamin D and its derivatives, vitamin E and its derivatives, and vitamin K and its derivatives.

[0019] In some embodiments, the antioxidant includes one or more of tocopherol, ascorbic acid and its salts, palmitol ascorbyl, butylated hydroxytoluene, propyl gallate, and butylated hydroxyanisole.

[0020] In some embodiments, the fat-soluble vitamin preparation intermediate comprises, by weight, 0.005-1 parts of fat-soluble vitamins, 95-99.995 parts of cyclodextrin derivatives, and 0.02-4 parts of antioxidants.

[0021] In some embodiments, the fat-soluble vitamin preparation intermediate is prepared by a granulation process.

[0022] In some embodiments, the granulation process comprises the following steps:

[0023] Step 1: mixing fat-soluble vitamins, antioxidants and solvents to prepare a solution;

[0024] Step 2: Using a cyclodextrin derivative as a substrate, adding a solution of fat-soluble vitamins and antioxidants to the substrate, mixing and granulating to obtain wet granules;

[0025] Step 3: Dry the wet particles.

[0026] In some embodiments, the solvent in step 1 comprises one or more of ethanol, acetone, glycerol, vegetable oil, medium-chain triglycerides, or hydrogenated soybean oil.

[0027] In some embodiments, the cyclodextrin derivative in step 2 is in a dry powder state.

[0028] In some embodiments, the mixing granulation method in step 2 includes one or more of extrusion granulation, high-speed stirring granulation or fluidized bed granulation.

[0029] It can be understood that the extrusion granulation is to use a solution to make the powder of the raw materials and auxiliary materials into a soft material, and then force the soft material through a screen or holes of a certain size by forced extrusion to form granules; high-speed stirring granulation is to mix the raw materials and auxiliary materials powder with a solution under the action of a high-speed rotating stirrer and cutter to obtain granules; fluidized bed granulation is to spray a solution into the powder in a fluidized state due to the action of airflow to obtain granules.

[0030] In some embodiments, the drying method in step three includes one or more of oven drying, fluidized bed drying, vacuum drying, freeze drying or air flow drying.

[0031] In some embodiments, the granulation process comprises the following steps:

[0032] Step 1: mixing fat-soluble vitamins, antioxidants and solvents to prepare a solution;

[0033] Step 2: Using cyclodextrin derivative powder as a substrate, spraying a solution of fat-soluble vitamins and antioxidants into the cyclodextrin derivative powder by wet granulation to obtain wet granules;

[0034] Step 3: Dry the wet particles.

[0035] The present invention has the following advantages:

[0036] 1. The present invention obtains a fat-soluble vitamin preparation intermediate having better stability than commercially available products by preparing a solution of vitamin D and an antioxidant and granulating the solution with a cyclodextrin derivative;

[0037] 2. The preparation auxiliary materials of the fat-soluble vitamin preparation intermediate of the present invention are easily obtained, the preparation process is simple, the preparation cost can be greatly saved, and it is suitable for industrial production. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0039] As used herein, the terms "comprises," "including," "having," "containing" or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a listed element is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0040] The indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirement (i.e. the number of times they appear). Therefore, "a" or "an" should be interpreted as including one or at least one, and elements or components in the singular also include plural forms, unless the quantity clearly refers to only the singular form.

[0041] Example 1

[0042] Table 1 Prescription table of Example 1

[0043] Vitamin D3 and butylated hydroxytoluene (BHT) were dissolved in anhydrous ethanol to prepare 150 g of vitamin D3-BHT ethanol solution; the fluidized bed was turned on, the air volume was adjusted to make the cyclodextrin powder form a suspended fluidized state, the inlet air temperature was set to 30°C, the atomization pressure was set to 0.02 bar, and 150 g of vitamin D3-BHT ethanol solution was slowly sprayed into the hydroxypropyl-β-cyclodextrin powder through a spray gun. The inlet air temperature was increased to 60°C and dried for nearly 1.5 hours to obtain vitamin D3 particles.

[0044] The sample prepared in Example 1 and commercially available vitamin D3 granules (vitamin D3 powder, DSM Nutritional Products Ltd) were separately packaged in moisture-proof aluminum foil bags and placed together at 80°C. The relative content of vitamin D3 was measured after 0, 6, and 9 days to investigate stability. The results are shown in Table 2 below. The granules prepared in Example 1 had a 0-day content of 100.0%, and after being placed under the harsh conditions of 80°C for 9 days, the granule content remained almost unchanged. The commercially available vitamin D3 granules had a 0-day content of 106.5%, and after being placed under the harsh conditions of 80°C for 9 days, the granule content decreased by nearly 9%. This shows that the stability of the vitamin D3 granules provided in Example 1 is superior to that of the commercially available preparation.

[0045] Table 2 Comparison of stability test results

[0046] Example 2

[0047] Table 3 Prescription of Example 2

[0048] Vitamin D3 and butylated hydroxytoluene (BHT) were dissolved in anhydrous ethanol to prepare 300 g of vitamin D3-BHT ethanol solution. The fluidized bed was turned on and the air volume was adjusted to make the cyclodextrin powder form a suspended fluidized state. The inlet air temperature was set to 30°C and the atomization pressure was set to 0.02 bar. After 300 g of vitamin D3-BHT ethanol solution was slowly sprayed into the hydroxypropyl-β-cyclodextrin powder through a spray gun, the inlet air temperature was increased to 65°C and dried for nearly 1 hour to obtain vitamin D3 particles.

[0049] The samples prepared in Example 2 and commercially available vitamin D3 granules (vitamin D3 powder, DSM Nutritional Products Ltd) were separately packaged in moisture-proof aluminum foil bags and placed together at 80°C. The relative content of vitamin D3 was measured after 0, 6, and 9 days of placement to investigate stability. The results are shown in Table 4 below. The 0-day content of the granules prepared in Example 2 was 100.0%, and after 9 days of placement, the change in granule content did not exceed 2%. The 0-day content of the commercially available vitamin D3 granules was 109.8%, and after 9 days of placement, the granule content decreased by about 13%. This shows that the stability of the vitamin D3 granules provided in Example 2 of the present invention is superior to that of the commercially available preparation.

[0050] Table 4 Comparison of stability test results

[0051] Example 3

[0052] Table 5 Prescription of Calcium Carbonate Chewable Tablets

[0053] Preparation method: Calcium carbonate, mannitol, and povidone are placed in a high-shear wet mixing granulator and mixed. Purified water is added and wet granules are formed by stirring and shearing. The granules are taken out and dried at 65°C in a fluidized bed for 30 minutes. The granules are then granulated in a granulator to obtain dry granules. The dry granules are then placed in a mixer with vitamin D3 granules / commercially available vitamin D3 granules, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and flavors and mixed for 16 minutes. The granules are then pressed into round tablets with a diameter of 16 mm.

[0054] The sample prepared in Example 1 and commercially available vitamin D3 particles (vitamin D3 powder, DSM Nutritional Products Ltd) were separately fed into the preparation to prepare calcium carbonate D3 chewable tablets, which were packaged in high-density polyethylene bottles and placed together at 40°C / 75% RH. The relative content of vitamin D3 in the preparations after 0, 3, and 6 months was measured for stability. The results are shown in Table 6 below, where the preparation prepared using the particles prepared in Example 1 had a 0-day content of 97.4%, and after being placed at 40°C for 6 months, the content of the preparation had almost no decrease. The preparation prepared from commercially available vitamin D3 particles had a 0-day content of 109.7%, and after being placed at 40°C for 6 months, the content of the preparation decreased by about 20%. This shows that the fat-soluble vitamin solid particles provided by the present invention are better in stability in the preparation than commercially available preparations, that is, the fat-soluble vitamin solid particles provided by the present invention have good applicability in the preparation.

[0055] Table 6 Comparison of stability test results Note: There is a certain deviation in the content detection by HPLC method, resulting in a slight difference of 97.4% on day 0 and 98.7% on month 6.

[0056] Example 4

[0057] Table 7 Example 4 Prescription

[0058] Vitamin A palmitate and propyl gallate were dissolved in anhydrous ethanol to prepare 50 g of vitamin A palmitate-B propyl gallate ethanol solution. The atomization pressure was set to 0.5 bar. After slowly and evenly spraying 50 g of vitamin A palmitate-B propyl gallate ethanol solution into hydroxypropyl-β-cyclodextrin powder through a spray gun, the stirring paddle speed was set to 180 rpm and the cutting knife speed was set to 200 rpm for granulation for 10 minutes. The powder was taken out and placed in a fluidized bed with an inlet air temperature set to 65°C and dried for 20 minutes to obtain vitamin A palmitate granules.

[0059] The samples prepared in Example 4 were packaged in moisture-proof aluminum foil bags along with commercially available vitamin A granules (vitamin A powder, BASF (China) Co., Ltd.). The samples were then stored at 50°C, and the relative content of vitamin A palmitate was measured after 0, 6, and 9 days to assess their stability. The results are shown in the table below. The granules prepared in Example 4 had a 0-day content of 100.0%, and after storage, the content of the granules varied within 3%. In contrast, the commercially available vitamin A powder had a 0-day content of 109.8%, and after 9 days, the content decreased by approximately 14%. This demonstrates that the vitamin A palmitate granules provided in Example 4 of the present invention are more stable than the commercially available formulation.

[0060] Table 8 Comparison of stability test results

[0061] Example 5

[0062] Table 9 Example 5 Prescription

[0063] Vitamin E and butylated hydroxyanisole were dissolved in anhydrous ethanol to prepare 180 g of vitamin E-butylated hydroxyanisole ethanol solution, and vitamin E particles were prepared by the preparation method of Example 1.

[0064] The samples prepared in Example 5 and commercially available vitamin E granules (vitamin E powder, BASF (China) Co., Ltd.) were separately packaged in moisture-proof aluminum foil bags and placed together at 40°C. The relative content of vitamin D3 was measured after 0, 3, and 6 months of placement to investigate stability. The results are shown in the table below. The granules prepared in Example 5 had a 0-day content of 100.0%, and after 6 months of placement, the granule content remained almost unchanged. The commercially available vitamin E granules had a 0-day content of 109.8%, and after 6 months of placement, the granule content decreased by about 10%. This indicates that the stability of the vitamin E granules provided in Example 5 of the present invention is superior to that of the commercially available preparation.

[0065] Table 10 Comparison of stability test results Note: There is a certain deviation in the content detection by HPLC method, resulting in slight differences of 100.1% on day 0 and 100.4% in March.

[0066] Example 6

[0067] Table 11 Prescription table of Example 6

[0068] Vitamin E and butylated hydroxytoluene (BHT) were dissolved in anhydrous ethanol to prepare 180 g of vitamin E-BHT ethanol solution, and vitamin E particles were prepared by the preparation method of Example 1.

[0069] The samples prepared in Example 6 were packaged in moisture-proof aluminum foil bags and stored at 80°C. The relative vitamin E content was measured after 0, 6, and 9 days to assess stability. The results are shown in the table below. The vitamin E content of the granules prepared in Example 6 was 93.5% on day 0, and after 9 days, the content had changed by more than 10%. The vitamin E granules prepared using the low-dosage cyclodextrin provided in Example 6 exhibited poor stability.

[0070] Table 12 Comparison of stability test results

[0071] Comparative Example 1

[0072] Table 13 Prescription table of comparative example 1

[0073] Vitamin D3 was dissolved in anhydrous ethanol to prepare a 120g vitamin D3 ethanol solution; the fluidized bed was turned on, the air volume was adjusted to make the cyclodextrin powder form a suspended fluidized state, the inlet air temperature was set to 30°C, the atomization pressure was set to 0.02 bar, and 120g of the vitamin D3 ethanol solution was slowly sprayed into the hydroxypropyl-β-cyclodextrin powder through a spray gun. The inlet air temperature was increased to 60°C and dried for nearly 1.5 hours to obtain vitamin D3 particles.

[0074] Comparative Example 2

[0075] The prescription of Comparative Example 2 is consistent with that of Example 1.

[0076] Preparation method: Vitamin D3 is dissolved in anhydrous ethanol to prepare a vitamin D3 ethanol solution, the vitamin D3 ethanol solution is sprayed into hydroxypropyl-β-cyclodextrin powder in a fluidized bed manner, and then mixed with butylated hydroxytoluene and dried to obtain vitamin D3 particles.

[0077] The above process is not feasible. Vitamin D3 is heat-sensitive. If it is directly involved in granulation and drying without the protection of antioxidants, it will be in a heated environment for a long time and is prone to degradation during the production process. As a result, the 0-day content of the prepared product is too low relative to the theoretical amount, which does not meet the requirements.

[0078] Comparative Example 3

[0079] The prescription of Comparative Example 3 is consistent with that of Example 1.

[0080] Preparation method: dissolve the antioxidant in anhydrous ethanol to prepare an antioxidant ethanol solution, spray the antioxidant ethanol solution into hydroxypropyl-β-cyclodextrin powder in a fluidized bed manner and dry it, and then mix it with vitamin D3 to obtain vitamin D3 particles.

[0081] The above process is not feasible. In essence, this process is a binary mixture formed by directly mixing vitamin D3 with hydroxypropyl-β-cyclodextrin powder containing dibutylhydroxytoluene. Vitamin D3 still exists in the form of raw material and is not protected by antioxidants. The product stability is poor and does not meet the requirements.

[0082] Comparative Example 4

[0083] The prescription of Comparative Example 4 is consistent with that of Example 1.

[0084] Preparation method: Vitamin D3, butylated hydroxytoluene and hydroxypropyl-β-cyclodextrin powder are mixed, sprayed into ethanol solution in a fluidized bed manner and dried to produce vitamin D3 particles.

[0085] The above process is not feasible because the dosage of vitamin D3 is extremely low (0.001-5 parts) and the raw material particle size is usually fine. It is easy to adhere to the inner wall of the equipment under long-term fluidized motion, resulting in poor product content uniformity and product content loss, which does not meet the requirements.

[0086] Comparative Example 5

[0087] An attempt was made to dissolve hydroxypropyl-β-cyclodextrin and butylated hydroxytoluene (BHT) in anhydrous ethanol to prepare hydroxypropyl-β-cyclodextrin-BHT ethanol solution, spray the hydroxypropyl-β-cyclodextrin-BHT ethanol solution into vitamin D3 powder using a fluidized bed spraying method and dry it to obtain vitamin D3 particles.

[0088] The above process has poor feasibility because the dosage of vitamin D3 is extremely low (0.001-5 parts), while the dosage of hydroxypropyl-β-cyclodextrin is relatively high (90-99.995 parts). The difference in dosage is too large. If hydroxypropyl-β-cyclodextrin and butylated hydroxytoluene (BHT) are prepared into an ethanol solution and then sprayed into vitamin D3, it is equivalent to completely dissolving the vitamin D3 to form a vitamin D3-cyclodextrin-BHT ethanol solution, rather than forming a granular state.

[0089] Comparative Example 6

[0090] Table 14 Prescription table of comparative example 6

[0091] Vitamin D3, butylated hydroxytoluene (BHT), and hydroxypropyl-β-cyclodextrin were dissolved in anhydrous ethanol to prepare 150 g of vitamin D3-BHT-cyclodextrin ethanol solution, which was added to 280 g of mannitol, mixed evenly, and then placed in an oven at 60°C for nearly 24 hours. The solution was then crushed to D90 < 40 μm to obtain vitamin D3 particles.

[0092] Comparative Example 7

[0093] Table 15 Prescription table of comparative example 7

[0094] Vitamin D3, butylated hydroxytoluene (BHT), and hydroxypropyl-β-cyclodextrin were dissolved in anhydrous ethanol to obtain 500 g of vitamin D3-BHT-cyclodextrin ethanol solution, and the solution was spray-dried to obtain vitamin D3 particles.

[0095] Stability test

[0096] The samples prepared in Comparative Examples 1, 6, and 7, along with those in Example 1, were packaged in moisture-proof aluminum foil bags and placed under the harsh conditions of 80°C. The changes in vitamin D3 content in the products were examined after 0, 6, and 9 days. As shown in Table 16 below, the stability of the vitamin D3 granules obtained in Comparative Example 1, without the addition of an antioxidant, was significantly worse than that of Example 1. The stability of the vitamin D3 granules obtained in Comparative Example 6, when mixed with a vitamin D3-BHT-cyclodextrin ethanol solution using other substances as substrates, was also significantly worse than that of Example 1. The vitamin D3 granules prepared in Comparative Example 7 via a spray-drying granulation process showed the worst stability, with the maximum content drop reaching nearly 25%.

[0097] Table 16 Comparison of stability test results

Claims

1. A fat-soluble vitamin preparation intermediate, characterized in that: The fat-soluble vitamin preparation intermediate comprises, by weight, 0.001-5 parts of fat-soluble vitamins, 90-99.995 parts of cyclodextrin derivatives and 0.004-5 parts of antioxidants.

2. The fat-soluble vitamin preparation intermediate according to claim 1, characterized in that: The cyclodextrin derivatives include β-cyclodextrin.

3. The fat-soluble vitamin preparation intermediate according to claim 1, characterized in that: The fat-soluble vitamins include one or more of vitamin A and its derivatives, vitamin D and its derivatives, vitamin E and its derivatives, and vitamin K and its derivatives.

4. The fat-soluble vitamin preparation intermediate according to claim 1, characterized in that: The antioxidant includes one or more of tocopherol, ascorbic acid and its salt, ascorbyl palmitate, butylated hydroxytoluene, propyl gallate, and tert-butyl p-hydroxyanisole.

5. The fat-soluble vitamin preparation intermediate according to claim 1, characterized in that: The fat-soluble vitamin preparation intermediate comprises, by weight, 0.005-1 parts of fat-soluble vitamins, 95-99.995 parts of cyclodextrin derivatives and 0.02-4 parts of antioxidants.

6. The fat-soluble vitamin preparation intermediate according to any one of claims 1 to 5, characterized in that: The fat-soluble vitamin preparation intermediate is prepared by a granulation process.

7. The fat-soluble vitamin preparation intermediate according to claim 6, characterized in that: The granulation process comprises the following steps: Step 1: mixing fat-soluble vitamins, antioxidants and solvents to prepare a solution; Step 2: using a cyclodextrin derivative as a substrate, adding the solution of fat-soluble vitamins and antioxidants obtained in step 1 to the substrate, mixing and granulating to obtain wet granules; Step 3: Drying the wet particles.

8. The fat-soluble vitamin preparation intermediate according to claim 7, characterized in that: The solvent in step 1 includes one or more of ethanol, acetone, glycerol, vegetable oil, medium-chain triglycerides or hydrogenated soybean oil.

9. The fat-soluble vitamin preparation intermediate according to claim 7, characterized in that: In the step 2, the cyclodextrin derivative is in a dry powder state.

10. The fat-soluble vitamin preparation intermediate according to claim 7, characterized in that: The mixing granulation method in step 2 includes one or more of extrusion granulation, high-speed stirring granulation or fluidized bed granulation.

11. The fat-soluble vitamin preparation intermediate according to claim 7, characterized in that: The drying method in step 3 includes one or more of oven drying, fluidized bed drying, vacuum drying, freeze drying or air flow drying.

12. The fat-soluble vitamin preparation intermediate according to claim 7, characterized in that: The granulation process comprises the following steps: Step 1: mixing fat-soluble vitamins, antioxidants and solvents to prepare a solution; Step 2: using cyclodextrin derivative powder as a substrate, spraying a solution of fat-soluble vitamins and antioxidants into the cyclodextrin derivative powder by wet granulation to obtain wet granules; Step 3: Drying the wet particles.

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