Preparation method of vitamin A acetate water-soluble powder

Abstract

The invention discloses a preparation method of vitamin A acetate water-soluble powder, which comprises the following specific operation processes: adding vitamin A acetate, an antioxidant, an inclusion material and an anti-caking agent into a ball-milling tank according to a feeding ratio, adding zirconium oxide beads as a ball-milling medium, sealing, placing the ball-milling tank on a roller ball mill, and carrying out ball milling to obtain the vitamin A acetate water-soluble powder. And carrying out ball milling to obtain the vitamin A acetate water-soluble powder. According to the present invention, the drug and the cyclodextrin are prepared into the inclusion compound through the mechanical force effect, such that the uniform dispersion and the encapsulation efficiency of the system are significantly improved, the stability, the solubility, the dissolution rate and the bioavailability of the vitamin A acetate are improved, and the preparation process has characteristics of short time consumption, no solvent, low drug loss and low production cost.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation preparation, and particularly relates to a method for preparing vitamin A acetate water-soluble powder. Background Art

[0002] Vitamin A is an important and easily deficient fat-soluble vitamin. It is necessary for animal bone growth, reproduction and embryonic development. It has the effect of enhancing animal antiviral ability and inhibiting fat synthesis. Animals lacking vitamin A can cause various diseases. Studies have shown that lack of vitamin A can easily affect animal reproduction. Adding an appropriate amount of vitamin A feed additive during animal husbandry can meet the growth needs of farmed animals, thereby greatly reducing animal breeding costs. In feed additives, relatively stable vitamin A acetate is often used, but vitamin A acetate has 5 conjugated double bonds and an ester group, and is still susceptible to damage by light, metal salts, peroxides and thermal catalysis. Therefore, there are certain problems in the storage of vitamin A feed additives. Antioxidants, macromolecular carriers and other excipients are often added to the market to make microgranules to improve their stability, but the vitamin A acetate feed additive prepared by this method is not easily soluble in water and is not suitable for drinking water administration. Xu et al. used freeze-drying coprecipitation to prepare inclusion complexes of vitamin A, vitamin A acetate and vitamin A palmitate with β-cyclodextrin, which improved solubility and thermal stability. (X.Xu, S.Peng and G.Bao et al., β-cyclodextrin inclusion complexes with vitamin A and its esters: a comparative experimental and molecular modeling study, Journal of Molecula r Structure, 2021, 1223, 129001.), but this method has complex steps and uses a large amount of organic solvents. Asli et al. used two derivatives of CD: HP-β-CD and HP-γ-CD to develop fast-dissolving and antioxidant nanofibrous webs of vitamin A acetate-CD inclusion complexes (Asli Celebioglu. Design of polymer-free Vitamin-A acetate / cyclodextrin nanofibrous webs: antioxidant and fast-dissolving properties. Food Function, 2020, 11, 7626-7637), but this method is costly and not suitable for continuous production. Zhou Huiming used high-pressure homogenization and spray drying to obtain vitamin A acetate microcapsules with high encapsulation rate. The product obtained by this method has a small particle size, but is easy to absorb moisture and has poor stability (CN200610097773.1).

[0003] Developing a delivery system in the form of a complex of poorly soluble drugs and solubilizing excipients is an effective method to improve the solubility of poorly soluble substances. The introduction of hydroxypropyl in hydroxypropyl-β-cyclodextrin breaks the intramolecular cyclic hydrogen bonds of β-cyclodextrin, while maintaining the cyclodextrin cavity and overcoming the main disadvantage of β-cyclodextrin's poor water solubility. It is one of the most intensively studied and widely used cyclodextrin derivatives, mainly used in the pharmaceutical and cosmetic industries as a stabilizer, emulsifier, deodorant, etc. Hydroxypropyl-β-cyclodextrin can improve the stability and long-term effectiveness of nutritional molecules, prevent the volatilization and oxidation of nutritional ingredients; it can mask or correct the bad smell and taste of food nutritional molecules, and improve the production process and product quality. Hydroxypropyl-β-cyclodextrin has a good solubility in water, which can improve the water solubility of poorly soluble drugs, increase drug stability, improve drug bioavailability, increase the efficacy of the drug or reduce the dosage, and can adjust or control the release rate of the drug and reduce the toxic and side effects of the drug. It can be used as a carrier for oral drugs, injections, mucosal drug delivery systems (including nasal mucosa, rectum, cornea, etc.), transdermal absorption drug delivery systems, and lipophilic targeted drugs.

[0004] Common methods for preparing vitamin A acetate inclusion complexes include saturated aqueous solution method, spray drying method, freeze drying method, and ultrasonic method. These methods are relatively complicated and require the use of organic solvents. However, the use of mechanical ball milling to produce vitamin A acetate water-soluble powder in a solvent-free manner can avoid the impact of organic solvents on the environment during the production process. This method is an innovation in the production process of vitamin A acetate powder. Summary of the invention

[0005] In view of the poor stability and solubility of vitamin A acetate, the present invention aims to provide a method for preparing a water-soluble powder of vitamin A acetate. The present invention rotates a suitable carrier, increases the uniform dispersibility of the drug and the carrier through mechanical force, fully encapsulates the drug and the inclusion material, and improves the stability, solubility, dissolution and bioavailability of vitamin A acetate.

[0006] The specific technical solutions are as follows:

[0007] A method for preparing vitamin A acetate water-soluble powder comprises the following steps: adding vitamin A acetate, an antioxidant, a inclusion material, and an anti-caking agent into a ball mill according to a feed ratio, and adding zirconium oxide beads as a ball milling medium; sealing the ball mill and placing the ball mill on a drum ball mill for ball milling, and obtaining the vitamin A acetate water-soluble powder after ball milling.

[0008] Furthermore, the mass ratio of vitamin A acetate, antioxidant, anti-caking agent and inclusion material is 1:0.2:0.1-0.2:4-4.4.

[0009] Furthermore, the antioxidant is one or more of sodium bisulfite, sodium thiosulfate, sodium ascorbate, butylated hydroxyanisole, butylated cresol, ethoxyquinoline, nordihydroguaiaretic acid, and tocopherol, preferably sodium ascorbate; the anti-caking agent is one or more of tricalcium phosphate, microcrystalline cellulose, silicon dioxide, magnesium stearate, and talc, preferably microcrystalline cellulose; the inclusion material is one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin sodium, preferably hydroxyethyl-β-cyclodextrin.

[0010] Furthermore, the filling rate of the ball mill is 10-90%, preferably 30-60%, and the mass ratio of the zirconium oxide beads to the total material is 10-30:1, preferably 15:1.

[0011] Furthermore, the ball milling time is 0.5-2.5 h, preferably 1.5 h, and the ball milling speed is 50-250 rpm, preferably 100-150 rpm.

[0012] The beneficial effects of the present invention are:

[0013] 1) The present invention increases drug stability by means of antioxidants and inclusion materials, and at the same time utilizes inclusion materials to increase its dissolution rate and solubility, which is beneficial to improving the bioavailability of vitamin A acetate in the body;

[0014] 2) The present invention prepares vitamin A acetate water-soluble powder by a limited preparation method, which is simple to operate and, compared with traditional preparations, does not require the use of solvents, has a simple process, and does not generate three wastes;

[0015] 3) The present invention ball-mills vitamin A acetate and inclusion materials by mechanical ball milling, which provides a new idea and method for the development of the production process of vitamin A acetate feed additive. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a schematic diagram of the dissolution results of vitamin A acetate prepared in Examples 1-9;

[0017] Figure 2 Schematic diagram of the bioavailability of vitamin A acetate prepared in Examples 1-9. DETAILED DESCRIPTION

[0018] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but the protection scope of the present invention is not limited thereto.

[0019] Example 1: Preparation of vitamin A acetate powder using α-cyclodextrin as inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: α-cyclodextrin = 1:0.2:0.1:4).

[0020] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and α-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.15mg / mL.

[0021] Example 2: Preparation of vitamin A acetate powder using β-cyclodextrin as inclusion material (vitamin A acetate sodium ascorbate: microcrystalline cellulose: β-cyclodextrin = 1:0.2:0.1:4).

[0022] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.24mg / mL.

[0023] Example 3: Preparation of vitamin A acetate powder using γ-cyclodextrin as inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: γ-cyclodextrin = 1:0.2:0.1:4).

[0024] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and γ-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.05mg / mL.

[0025] Example 4: Preparation of vitamin A acetate powder using hydroxypropyl-β-cyclodextrin as inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: hydroxypropyl-β-cyclodextrin = 1:0.2:0.1:4).

[0026] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and hydroxypropyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.31mg / mL.

[0027] Example 5: Preparation of vitamin A acetate powder using hydroxyethyl-β-cyclodextrin as inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: hydroxyethyl-β-cyclodextrin = 1:0.2:0.1:4).

[0028] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and hydroxyethyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.37mg / mL.

[0029] Example 6: Vitamin A acetate powder was prepared using 2,6-dimethyl-β-cyclodextrin as an inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: 2,6-dimethyl-β-cyclodextrin = 1:0.2:0.1:4).

[0030] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and 2,6-dimethyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type roller ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 0.93mg / mL.

[0031] Example 7: Preparation of vitamin A acetate powder using sodium sulfobutyl-β-cyclodextrin as inclusion material (vitamin A acetate: sodium ascorbate: microcrystalline cellulose: sulfobutyl-β-cyclodextrin = 1:0.2:0.1:4).

[0032] Add vitamin A acetate (9.10g), sodium ascorbate (2.02g), microcrystalline cellulose (1.01g) and sodium sulfobutyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type drum ball mill, set the speed to 100rpm, and the time is 1.5h. After the ball milling is completed, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use high performance liquid chromatography for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 0.73mg / mL.

[0033] Example 8: Preparation of vitamin A acetate powder using hydroxyethyl-β-cyclodextrin as inclusion material (vitamin A acetate: ethoxyquinoline: microcrystalline cellulose: β-cyclodextrin = 1:0.2:0.1:4).

[0034] Add vitamin A acetate (9.10g), ethoxyquinoline (2.02g), microcrystalline cellulose (1.01g) and hydroxyethyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type roller ball mill, set the speed to 150rpm, and the time is 2h. After the ball milling, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in a 100mL supported conical bottle, add 50mL of distilled water, seal it and place it in a 37℃ air bath constant temperature oscillator, and shake it at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.35mg / mL.

[0035] Example 9: Preparation of vitamin A acetate powder using hydroxyethyl-β-cyclodextrin as inclusion material (vitamin A acetate: tocopherol: microcrystalline cellulose: β-cyclodextrin = 1:0.2:0.1:4).

[0036] Add vitamin A acetate (9.10g), tocopherol (2.02g), microcrystalline cellulose (1.01g) and hydroxyethyl-β-cyclodextrin (36.00g) to the ball mill, add 753.5g of zirconia beads with a diameter of 15mm as grinding media, the filling rate is 30%, mix well and put into GMS1-4 type roller ball mill, set the speed to 150rpm, and the time is 2h. After the ball milling, take an appropriate amount of vitamin A acetate water-soluble powder (the powder can form a saturated solution in water) in 100mL. Add 50mL of distilled water to a conical flask with a support, seal it and place it in a 37℃ air bath constant temperature oscillator, and oscillate at a speed of 160rpm for 24 hours. Take the supernatant and pass it through a 0.22μm needle filter and use a high performance liquid chromatograph for analysis. The experimental results show that the solubility of vitamin A acetate under this component is 1.33mg / mL.

[0037] Example 10: Stability Study of Vitamin A Acetate Water-Soluble Powder

[0038] In Examples 1-7, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin sodium are selected as the packaging material of vitamin A acetate, and water-soluble vitamin A acetate powder containing different excipients is prepared. In Examples 8-9, different antioxidants are used to prepare water-soluble vitamin A acetate powder. An appropriate amount of each water-soluble vitamin A acetate powder is put into an aluminum foil bag, vacuum-sealed, and placed in a 60°C oven for stability testing. The bags are taken out on the 5th, 10th, 20th, and 30th days of placement, and the content of vitamin A acetate is detected using a high performance liquid chromatograph. From the results, it can be seen that the content retention rate of vitamin A acetate is above 80% for all formulas under high temperature conditions for 30 days. It shows that the vitamin A acetate powder prepared by ball milling has good stability.

[0039] Table 1 Summary of stability test results of products prepared by different embodiments

[0040] Example Vitamin A acetate retention after 30 days % Vitamin A Acetate Raw Material 43.8％ Example 1 86.43 Example 2 85.09 Example 3 81.98 Example 4 83.52 Example 5 85.25 Example 6 85.07 Example 7 85.69 Example 8 84.75 Example 9 70.53

[0041] Example 11: Dissolution Study of Vitamin A Acetate Water-Soluble Powder

[0042] In Examples 1-7, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin sodium are used as the packaging material of vitamin A acetate to prepare water-soluble vitamin A acetate powder containing different excipients. In Examples 8-9, different antioxidants are used to prepare water-soluble vitamin A acetate powder. A small amount of each water-soluble vitamin A acetate powder and vitamin A acetate raw material is taken and the dissolution is measured using a dissolution apparatus. The temperature of the dissolution apparatus is set to 37°C, the rotation speed is set to 100 rpm, and the content of vitamin A acetate is measured using an ultraviolet spectrophotometer. Under this condition, the solubility of the vitamin A acetate raw material in water is extremely low, and the solubility is zero, while from Figure 1 It can be seen that the solubility of the vitamin A acetate water-soluble powder prepared by ball milling is almost all above 60%.

[0043] Example 12: Bioavailability Study of Vitamin A Acetate Water-Soluble Powder

[0044] In Examples 1-7, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin sodium were used as the packaging materials for vitamin A acetate. In Examples 8-9, different antioxidants were used to prepare water-soluble vitamin A acetate powders containing different excipients for bioavailability experiments. Rats were fasted for 12 hours before the experiment and had free access to water. The dosage was calculated as vitamin A acetate and was set at 5000 IU / kg. Rats were given a single oral gavage. 1.0 mL of blood was collected from the eyelids at 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 5 hours, 7 hours, 10 hours, and 24 hours after administration. The plasma was collected in centrifuge tubes containing sodium heparin and processed. The content of vitamin A acetate was determined using a high performance liquid chromatograph. Figure 2 It can be seen that the maximum blood drug concentration of vitamin A acetate water-soluble powder prepared by ball milling is greater than that of vitamin A acetate raw material, indicating that the water-soluble property prepared by ball milling has improved the bioavailability of vitamin A acetate to a certain extent.

Claims

1. A method for preparing vitamin A acetate water-soluble powder, characterized in that: The method comprises the following steps: adding vitamin A acetate, an antioxidant, a clathrate material and an anti-caking agent into a ball mill according to the feed ratio, and adding zirconium oxide beads as ball milling media; sealing the ball mill and placing the ball mill on a drum ball mill for ball milling, and obtaining vitamin A acetate water-soluble powder after ball milling.

2. The method for preparing a water-soluble vitamin A acetate powder according to claim 1, wherein: The mass ratio of vitamin A acetate, antioxidant, anti-caking agent and inclusion material is 1:0.2:0.1-0.2:4-4.

4.

3. A method for preparing a water-soluble vitamin A acetate powder as claimed in claim 1 or 2, characterized in that: The antioxidant is one or more of sodium bisulfite, sodium thiosulfate, sodium ascorbate, butylated hydroxyanisole, butylated cresol, ethoxyquinoline, nordihydroguaiaretic acid, and tocopherol, preferably sodium ascorbate; the anticaking agent is one or more of tricalcium phosphate, microcrystalline cellulose, silicon dioxide, magnesium stearate, and talc, preferably microcrystalline cellulose; the inclusion material is one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin sodium, preferably hydroxyethyl-β-cyclodextrin.

4. The method for preparing a water-soluble vitamin A acetate powder according to claim 3, wherein: The filling rate of the ball mill is 10-90%, preferably 30-60%, and the mass ratio of zirconium oxide beads to the total material is 10-30:1, preferably 15:

1.

5. The method for preparing a water-soluble vitamin A acetate powder according to claim 4, characterized in that: The ball milling time is 0.5-2.5 h, preferably 1.5 h, and the ball milling speed is 50-250 rpm, preferably 100-150 rpm.

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