Fat-soluble vitamin preparation intermediate and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a fat-soluble vitamin preparation intermediate and a preparation method thereof.The fat-soluble vitamin preparation intermediate is prepared from, by weight, 0.001-5 parts of fat-soluble vitamins, 90-99.995 parts of cyclodextrin derivatives and 0.004-5 parts of antioxidants; according to the invention, the fat-soluble vitamin, the antioxidant and the cyclodextrin derivative are utilized to form an inclusion compound, and the fat-soluble vitamin preparation intermediate which is simple in component, simple and convenient in process, suitable for industrial production and excellent in stability is obtained.

Description

Technical Field

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

[0002] Fat-soluble vitamins are substances that play a huge role in maintaining the normal functions of the human body. After entering the gastrointestinal tract, they dissolve in lipid micelles, are absorbed in the intestine by the emulsifying action of bile, and then enter various organs of the human body through the lymphatic system. Most of them are stored in adipose tissue, and only a small amount is excreted from the body. Fat-soluble vitamins mainly include vitamin A, vitamin D, vitamin E, vitamin K and their derivatives, and have the characteristics of being soluble in oils, insoluble in water, and having poor stability.

[0003] Generally speaking, the vitamins required by the human body daily can be supplemented from a normal diet and the demand is extremely small, often calculated in milligrams (mg) or micrograms (μg); for some special groups, such as infants, the elderly, and food preference people, the intake of fat-soluble vitamins often tends to be insufficient. If not supplemented additionally, vitamin deficiency symptoms may occur. Products for additional vitamin supplementation can be selected from medicines, health foods, and other foods with vitamins added as nutritional fortifiers.

[0004] Among various existing commercially available products, the addition forms of fat-soluble vitamins are mainly divided into two categories: raw materials and preparation intermediates. Feeding in the form of raw materials often has stability problems, resulting in a short shelf life of the finished product, or excessive feeding is adopted to ensure the content limit, bringing problems of production cost and safety of content exceeding the limit. Feeding with preparation intermediates can not only improve the stability of the finished product, extend the shelf life, but also simplify the production operation. However, among various commercially available vitamin preparation intermediates at present, such as fat-soluble vitamin granules, they are mostly made in the form of microcapsules, contain multiple components, and the preparation process is relatively complex. In addition, although their stability is better than that of the corresponding fat-soluble vitamin raw materials, the content still decreases during long-term storage and application.

[0005] Patent CN113730359A discloses a fat-soluble vitamin solid particle, 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 a low content specification. By means of spray drying, the particle size of the fat-soluble vitamin solid particles is reduced, and the risk of unqualified content uniformity in the mixing process is lowered. In addition, the relative content of the fat-soluble vitamin solid particles obtained by using two antioxidants with different oxidation potentials after stability placement is significantly better than that of commercially available products and comparative products. However, the fat-soluble vitamin solid particles disclosed in this patent contain multiple components, the preparation process is relatively complex, and the stability needs to be further improved.

[0006] Patent CN114668726A discloses a vitamin D3 mixed powder and its preparation method, which includes an aqueous phase component and an oil phase component. The aqueous phase component includes sodium octenyl succinate starch, sucrose and sodium ascorbate, and the oil phase component includes tocopherol, medium-chain triglyceride 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 condition during the conversion of the vitamin D3 emulsion into a powder, which can fully protect vitamin D3 in the vitamin D3 mixed powder, effectively avoid the loss of vitamin D3, and make the content of vitamin D3 in the finally prepared vitamin D3 mixed powder still 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 components, the preparation process is very complex, and the stability needs to be further improved.

[0007] Patent CN115581303A discloses a vitamin solid, its preparation method and application, which includes a vitamin, an oil, an antioxidant, an encapsulating agent, an emulsifier and a nucleating agent. It is believed that under the action of the nucleating agent, spray drying is carried out on the emulsion of the vitamin and its derivatives to obtain a stable vitamin core-shell structure, solving the problem of the decrease in the content of the vitamin during preparation and storage. However, the vitamin solid disclosed in this patent contains multiple components, the preparation process is relatively complex, and the stability needs to be further improved.

[0008] Patent GB2037773B discloses a process for preparing stable vitamin d and its composition, which includes forming a homogeneous solution of vitamin D to be complexed and cyclodextrin in an aqueous ethanol solution at a certain temperature, and separating the required inclusion complex from the solution by cooling and / or by evaporating the solvent. This preparation method requires heating the ethanol solution and uses a large amount of ethanol, and the operation is complex. On the one hand, there is a relatively high production safety risk, and on the other hand, there is also a relatively high application safety risk of ethanol residue in the produced product.

[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 dissolving in ethanol, filtering, concentrating under reduced pressure, drying with nitrogen, dissolving in ice water, filtering, and freeze-drying. The process is relatively cumbersome. The entire preparation process must be carried out under anaerobic and light-protected conditions, and it may cause the degradation of vitamin D, making it difficult to carry out large-scale production.

[0010] Therefore, there is an urgent need in the art for a vitamin preparation intermediate with simple components, simple process, suitable 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. By forming an inclusion complex of a fat-soluble vitamin, an antioxidant, and a cyclodextrin derivative, a fat-soluble vitamin preparation intermediate with simple components, simple process, suitable for industrial production, and excellent stability is obtained.

[0012] On the one hand, the present invention provides a fat-soluble vitamin preparation intermediate. The fat-soluble vitamin preparation intermediate includes 0.001-5 parts by weight of a fat-soluble vitamin, 90-99.995 parts by weight of a cyclodextrin derivative, and 0.004-5 parts by weight of an antioxidant.

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

[0014] It can be understood that the cyclodextrin derivative is a high-molecular substance. Its molecular structure has a conical ring-shaped cavity. The outside of the cavity is hydrophilic and the inside is hydrophobic. It can capture the fat-soluble vitamin molecules in the molecular cavity of the cyclodextrin derivative to form an inclusion complex. On the other hand, excessive cyclodextrin derivative molecules aggregate together to form a wall material-like structure, wrapping the fat-soluble vitamin molecules between the cyclodextrin derivative molecules, achieving the effect of isolating the fat-soluble vitamin molecules from contact with the outside world and preventing oxidation and degradation, thereby improving the stability of the fat-soluble vitamin. In particular, the addition of a compound of an antioxidant and a fat-soluble vitamin to form an inclusion complex with cyclodextrin can further improve the stability of the fat-soluble vitamin.

[0015] The weight portion of the fat-soluble vitamin is 0.001-5 parts, for example, it can be 0.001 part, 0.03 part, 0.4 part, 1 part, 2 part, 3 part, 4 part, or 5 part, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the above range.

[0016] The weight portion 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 the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said 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 part, 2 parts, 3 parts, or 5 parts, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0018] In some embodiments, the fat-soluble vitamin includes 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, ascorbyl palmitate, dibutylhydroxytoluene, propyl gallate, and tert-butyl-p-hydroxyanisole.

[0020] In some embodiments, the fat-soluble vitamin preparation intermediate includes 0.005 - 1 part of fat-soluble vitamin, 95 - 99.995 parts of cyclodextrin derivative, and 0.02 - 4 parts of antioxidant by weight.

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

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

[0023] Step 1: Mix the fat-soluble vitamin, antioxidant, and solvent to form a solution.

[0024] Step 2: Using the cyclodextrin derivative as a substrate, add the solution of the fat-soluble vitamin and antioxidant to the substrate and mix for granulation to obtain wet granules.

[0025] Step 3: Dry the above wet granules.

[0026] In some embodiments, the solvent in Step 1 includes one or more of ethanol, acetone, glycerol, vegetable oil, medium-chain triglyceride, 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 the second step 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 make the powder of raw and auxiliary materials into a soft material with a solution and then force the soft material to pass through a sieve or hole of a certain size to form granules by forced extrusion; the high-speed stirring granulation is to mix the powder of raw and auxiliary materials with a solution under the action of a high-speed rotating stirrer and cutter to obtain granules; the fluidized bed granulation is to spray a solution into the powder in a fluidized state formed by the action of air flow to obtain granules.

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

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

[0032] Step 1: Mix and prepare a solution of fat-soluble vitamins, antioxidants, and a solvent.

[0033] Step 2: Using cyclodextrin derivative powder as a substrate, spray the solution of fat-soluble vitamins and antioxidants into the cyclodextrin derivative powder in a wet granulation method to granulate and obtain wet granules.

[0034] Step 3: Dry the above wet granules.

[0035] The present invention has the following advantages:

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

[0037] 2. The preparation excipients of the fat-soluble vitamin preparation intermediate of the present invention are easily obtained, the preparation process is simple, and the preparation cost can be greatly saved, which is suitable for industrial production. Specific Embodiments

[0038] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0039] As used herein, the terms "comprising", "including", "having", "containing", or any other variation thereof are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus containing the listed elements is not necessarily limited to those elements, but may also include other elements not expressly listed or elements inherent to such composition, step, 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 requirements (i.e., the number of occurrences) of the elements or components. Therefore, "a" or "an" should be construed as including one or at least one, and the singular forms of the elements or components also include the plural forms, unless the quantity clearly refers only to the singular form.

[0041] Example 1

[0042] Table 1 Prescription Table of Example 1

[0043] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin D3 0.025 0.005 Butylated hydroxytoluene 0.1 0.02 Hydroxypropyl-β-cyclodextrin 500 99.975

[0044] Dissolve vitamin D3 and butylated hydroxytoluene (BHT) in absolute ethanol to prepare 150 g of vitamin D3-BHT ethanol solution; turn on the fluidized bed, adjust the air volume to make the cyclodextrin powder form a suspended fluidized state, set the inlet air temperature to 30 °C, set the atomization pressure to 0.02 bar, and slowly spray all 150 g of vitamin D3-BHT ethanol solution into the hydroxypropyl-β-cyclodextrin powder through a spray gun, then raise the inlet air temperature to 60 °C for drying for nearly 1.5 h to obtain vitamin D3 granules.

[0045] Pack the sample prepared in Example 1 and the commercially available vitamin D3 granules (vitamin D3 powder, DSM Nutritional Products Ltd) separately in moisture-proof aluminum foil bags, and place them together at 80 °C. Measure the relative content of vitamin D3 after 0, 6, and 9 days of placement respectively to conduct a stability investigation. The results are shown in Table 2 below. The content of the granules prepared in Example 1 at 0 day is 100.0%. After being placed at 80 °C under severe conditions for 9 days, the content of the granules hardly changes. While the content of the commercially available vitamin D3 granules at 0 day is 106.5%, and after being placed at 80 °C under severe conditions for 9 days, the content of the granules decreases by nearly 9%. This shows that the vitamin D3 granules provided in Example 1 have better stability than the commercially available preparation.

[0046] Table 2 Comparison Table of Stability Experiment Results

[0047]

[0048] Example 2

[0049] Table 3 Prescription Table of Example 2

[0050] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin D3 0.05 0.01 Butylated hydroxytoluene 0.2 0.04 Hydroxypropyl-β-cyclodextrin 500 99.95

[0051] Dissolve vitamin D3 and butylated hydroxytoluene (BHT) in absolute ethanol to prepare 300 g of vitamin D3-BHT ethanol solution. Start the fluidized bed, adjust the air volume to make the cyclodextrin powder form a suspended fluidized state, set the inlet air temperature to 30 °C, set the atomization pressure to 0.02 bar, and slowly spray 300 g of vitamin D3-BHT ethanol solution into hydroxypropyl-β-cyclodextrin powder through a spray gun. Then, raise the inlet air temperature to 65 °C and dry for nearly 1 h to obtain vitamin D3 granules.

[0052] The samples prepared in Example 2 and commercially available vitamin D3 granules (vitamin D3 powder, DSM Nutritional Products Ltd) were respectively 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 conduct a stability investigation. The results are shown in Table 4 below. The content of the granules prepared in this Example 2 was 100.0% at day 0, and after 9 days of placement, the change range of the granule content did not exceed 2%. The content of the commercially available vitamin D3 granules was 109.8% at day 0, and after 9 days of placement, the granule content decreased by approximately 13%. This indicates 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.

[0053] Table 4 Comparison table of stability experiment results

[0054]

[0055] Example 3

[0056] Table 5 Prescription table of calcium carbonate chewable tablets

[0057]

[0058]

[0059] Preparation method: Load calcium carbonate, mannitol, and polyvinylpyrrolidone into a high-shear wet granulation machine for mixing, add purified water, and make wet granules through stirring and shearing. Take out and dry at 65 °C in a fluidized bed for 30 min, then screen through a granulator to obtain dry granules. Mix the dry granules with vitamin D3 granules / commercially available vitamin D3 granules, cross-linked carboxymethylcellulose sodium, magnesium stearate, and essence in a mixer for 16 min, and press into circular tablets with a diameter of 16 mm.

[0060] The samples prepared in Example 1 and the commercially available vitamin D3 granules (vitamin D3 powder, DSM Nutritional Products Ltd) were separately fed into the preparation to obtain calcium carbonate D3 chewable tablets, which were respectively packaged in high-density polyethylene bottles and placed together under the conditions of 40°C / 75% RH. The relative content of vitamin D3 in the preparation after 0, 3, and 6 months of placement was measured respectively for stability investigation. The results are shown in Table 6 below. Among them, the content of the preparation prepared with the granules obtained in Example 1 was 97.4% on the 0th day, and after 6 months of placement at 40°C, the content of the preparation hardly decreased. While the content of the preparation prepared with the commercially available vitamin D3 granules was 109.7% on the 0th day, and after 6 months of placement at 40°C, the content of the preparation decreased by about 20%. This indicates that the stability of the fat-soluble vitamin solid granules provided by the present invention in the preparation is better than that of the commercially available preparation, that is, the fat-soluble vitamin solid granules provided by the present invention have good applicability in the preparation.

[0061] Table 6 Comparison Table of Stability Experiment Results

[0062]

[0063] Note: There is a certain deviation in the content detected by the HPLC method, and there is a slight difference in the situation of 97.4% on the 0th day and 98.7% after 6 months.

[0064] Example 4

[0065] Table 7 Prescription Table of Example 4

[0066] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin A palmitate 0.025 0.005 Propyl gallate 0.1 0.02 Hydroxypropyl-β-cyclodextrin 500 99.975

[0067] Dissolve vitamin A palmitate and propyl gallate in absolute ethanol to obtain 50 g of vitamin A palmitate-propyl gallate ethanol solution. Set the atomization pressure to 0.5 bar. Slowly and evenly spray 50 g of vitamin A palmitate-propyl gallate ethanol solution into hydroxypropyl-β-cyclodextrin powder through a spray gun. Then set the stirring blade speed to 180 rpm and the cutter speed to 200 rpm for granulation for 10 minutes. Take it out and place it in a fluidized bed, set the inlet air temperature to 65°C and dry for 20 minutes to obtain vitamin A palmitate granules.

[0068] The samples prepared in Example 4 and commercially available vitamin A granules (vitamin A powder, BASF (China) Co., Ltd.) were separately packaged in moisture-proof aluminum foil bags and placed together at 50 °C. The relative contents of vitamin A palmitate after 0, 6, and 9 days of placement were measured respectively for stability investigation. The results are shown in the following table. Among them, the content of the granules prepared in Example 4 was 100.0% at day 0, and after placement, the change range of the granule content was within 3%. The content of the commercially available vitamin A powder was 109.8% at day 0, and after 9 days of placement, the granule content decreased by about 14%. This indicates that the stability of the vitamin A palmitate granules provided in Example 4 of the present invention is superior to that of the commercially available preparation.

[0069] Table 8 Comparison table of stability experiment results

[0070]

[0071] Example 5

[0072] Table 9 Prescription table of Example 5

[0073] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin E 5 1 Butylated hydroxyanisole 20 4 Hydroxypropyl-β-cyclodextrin 475 95

[0074] Vitamin E and butylated hydroxyanisole were dissolved in absolute ethanol to prepare 180 g of vitamin E-butylated hydroxyanisole ethanol solution, and vitamin E granules were prepared by the preparation method of Example 1.

[0075] 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 contents of vitamin D3 after 0, 3, and 6 months of placement were measured respectively for stability investigation. The results are shown in the following table. Among them, the content of the granules prepared in Example 5 was 100.0% at day 0, and after 6 months of placement, the change in the granule content was almost negligible. The content of the commercially available vitamin E granules was 109.8% at day 0, 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.

[0076] Table 10 Comparison table of stability experiment results

[0077]

[0078] Note: There is a certain deviation in the content detection by HPLC method, and there is a slight difference of 100.1% at day 0 and 100.4% at 3 months.

[0079] Example 6

[0080] Table 11 Prescription table of Example 6

[0081] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin E 120 12.3 Butylated hydroxytoluene 2 0.2 Hydroxypropyl-β-cyclodextrin 850 87.5

[0082] Dissolve vitamin E and butylated hydroxytoluene (BHT) in absolute ethanol to obtain 180 g of vitamin E - BHT ethanol solution, and prepare vitamin E granules by the preparation method of Example 1.

[0083] The sample prepared in Example 6 was packaged in a moisture - proof aluminum foil bag and placed at 80 °C. The relative content of vitamin E was measured after 0, 6, and 9 days of placement to conduct a stability investigation. The results are shown in the following table. The content of the granules prepared in this Example 6 was 93.5% at 0 day. After 9 days of placement, the change range of the granule content exceeded 10%. The stability of the vitamin E granules prepared with low - dosage cyclodextrin provided in Example 6 of the present invention is poor.

[0084] Table 12 Comparison table of stability experiment results

[0085]

[0086] Comparative Example 1

[0087] Table 13 Prescription table of Comparative Example 1

[0088] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin D3 0.025 0.005 Hydroxypropyl-β-cyclodextrin 499.975 99.995

[0089] Dissolve vitamin D3 in absolute ethanol to obtain 120 g of vitamin D3 ethanol solution; turn on the fluidized bed, adjust the air volume to make the cyclodextrin powder form a suspended fluidized state, set the inlet air temperature to 30 °C, set the atomization pressure to 0.02 bar, and slowly spray all 120 g of vitamin D3 ethanol solution into the hydroxypropyl - β - cyclodextrin powder through a spray gun, then raise the inlet air temperature to 60 °C for drying for nearly 1.5 h to obtain vitamin D3 granules.

[0090] Comparative Example 2

[0091] The prescription of Comparative Example 2 is the same as that of Example 1.

[0092] Preparation method: Dissolve vitamin D3 in absolute ethanol to obtain vitamin D3 ethanol solution, spray the vitamin D3 ethanol solution into the hydroxypropyl - β - cyclodextrin powder in the way of loading medicine on the fluidized bed, then mix it with butylated hydroxytoluene and dry to obtain vitamin D3 granules.

[0093] The above process is not feasible. Vitamin D3 is heat - sensitive. Without the protection of an antioxidant, directly participating in granulation and drying, that is, being in a heating environment for a long time, it is easy to degrade during the production process, resulting in the content of the prepared product at 0 day being too low compared to the theoretical amount and not meeting the requirements.

[0094] Comparative Example 3

[0095] The prescription of Comparative Example 3 is the same as that of Example 1.

[0096] Preparation method: dissolving an antioxidant in anhydrous ethanol to prepare an antioxidant ethanol solution, spraying the antioxidant ethanol solution into hydroxypropyl-β-cyclodextrin powder in a fluidized bed manner and drying it, and then mixing it with vitamin D3 to obtain vitamin D3 particles.

[0097] The above process is not feasible. In essence, the process is a binary mixture formed by directly mixing vitamin D3 with hydroxypropyl-β-cyclodextrin powder containing butylated hydroxytoluene. Vitamin D3 still exists in the form of raw materials and is not protected by antioxidants. The product stability is poor and does not meet the requirements.

[0098] Comparative Example 4

[0099] The prescription of Comparative Example 4 is consistent with that of Example 1.

[0100] 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.

[0101] 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 state, resulting in poor product content uniformity and product content loss that does not meet the requirements.

[0102] Comparative Example 5

[0103] An attempt was made to dissolve hydroxypropyl-β-cyclodextrin and butylated hydroxytoluene (BHT) in anhydrous ethanol to obtain a hydroxypropyl-β-cyclodextrin-BHT ethanol solution, and then spray the hydroxypropyl-β-cyclodextrin-BHT ethanol solution into vitamin D3 powder by fluidized bed coating and dry it to obtain vitamin D3 particles.

[0104] The feasibility of the above process is poor 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.

[0105] Comparative Example 6

[0106] Table 14 Comparative Example 6 Prescription Table

[0107] Prescription composition Prescription quantity (g) Number of prescription copies Vitamin D3 0.05 0.01 Butylated hydroxytoluene 0.2 0.05 Hydroxypropyl-β-cyclodextrin 100 26.3 Mannitol 280 73.64

[0108] Dissolve vitamin D3, butylated hydroxytoluene (BHT), and hydroxypropyl-β-cyclodextrin in absolute ethanol to prepare 150 g of vitamin D3-BHT-cyclodextrin ethanol solution. Add it to 280 g of mannitol, mix evenly, then place it in an oven at 60 °C for drying for nearly 24 h, and pulverize it to D90 < 40 μm to obtain vitamin D3 granules.

[0109] Comparative Example 7

[0110] Table 15 Prescription Table of Comparative Example 7

[0111]

[0112]

[0113] Dissolve vitamin D3, butylated hydroxytoluene (BHT), and hydroxypropyl-β-cyclodextrin in absolute ethanol respectively to obtain 500 g of vitamin D3-BHT-cyclodextrin ethanol solution. Take the solution for spray drying to obtain vitamin D3 granules.

[0114] Stability experiment

[0115] Pack the samples prepared in Comparative Example 1, Comparative Example 6, Comparative Example 7 and Example 1 above in moisture-proof aluminum foil bags respectively, and place them under severe conditions at 80 °C to investigate the change of vitamin D3 content in the products after 0, 6, and 9 days of placement. As shown in Table 16 below, in the prescription without adding antioxidant in Comparative Example 1, the product stability is significantly worse than that of Example 1; when using other substances as substrates to mix vitamin D3-BHT-cyclodextrin ethanol solution in Comparative Example 6, the stability of the obtained vitamin D3 granules is also significantly worse than that of Example 1; the stability of the vitamin D3 granules prepared by the spray drying granulation process in Comparative Example 7 is the worst, and the maximum content reduction reaches nearly 25%.

[0116] Table 16 Comparison Table of Stability Experiment Results

[0117]

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-butylated 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, glycerin, vegetable oil, medium-chain triglyceride 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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