Vitamin E and C granules and preparation method thereof

Abstract

The invention provides vitamin E and C granules and a preparation method thereof. The vitamin E and C granules are prepared from the following components in parts by weight: 80 to 150 parts of vitamin E, 160 to 300 parts of vitamin C, 200 to 600 parts of hydroxy propyl cellulose and 1500 to 4000 parts of excipient. Vitamin E and vitamin C particles are prepared by compounding vitamin E, vitamin C and hydroxy propyl cellulose and adopting hot-melt extrusion, so that the temperature of hot-melt extrusion can be remarkably reduced, the vitamin C can be better protected from being oxidized, the hydrophilicity of the vitamin E subjected to melt extrusion can be remarkably improved, the dissolving property of the vitamin E in water can be promoted, and the dissolution rate of the vitamin E in water can be increased. Therefore, the problem of vitamin E dose loss caused by the fact that vitamin E floats on the liquid level or is adsorbed on the cup wall when the vitamin E and C granules are taken is solved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to vitamin E and C particles and a preparation method thereof. Background Art

[0002] Vitamins are a type of nutrients necessary to maintain normal metabolism and function of the human body. Although the required amount is low, the human body cannot synthesize them itself or the amount synthesized is insufficient, so they need to be obtained from the outside.

[0003] Vitamin E, also known as vitamin E or tocopherol, has antioxidant properties and can reduce free radical damage to cell membranes by inhibiting the formation of free radicals and the activity of restriction endonucleases. Vitamin E can eliminate lipofuscin in cells, has anti-aging effects, and can reduce the risk of habitual miscarriage. At the same time, vitamin E has a protective effect on the blood and vascular system, and has therapeutic effects on megaloblastic anemia, hemolytic anemia of premature infants, and favism. Vitamin C, also known as L-ascorbic acid, has strong reducing properties and participates in complex metabolic processes in the body. In the body, vitamin C can reduce other active oxides such as superoxide and hydroxyl groups, promote intestinal absorption of iron, prevent the formation of insoluble calcium complexes, promote the reduction of biologically active tetrahydrofolate by folic acid, maintain the integrity of blood vessels, and prevent and treat scurvy.

[0004] Vitamin E and vitamin C are both antioxidants, and their combined use can enhance their antioxidant effects. However, vitamin C is easily oxidized by air and loses its activity. Furthermore, due to their different physical and chemical properties, vitamin C is water-soluble while vitamin E is oil-soluble. Conventional granules prepared using water can easily cause the vitamin E to float to the surface of the liquid when taken with water, resulting in adhesion to the surface of the drinking container and loss of vitamin E. Therefore, it is necessary to develop a granule product that is simple to prepare, convenient to take, and has good stability. Summary of the Invention

[0005] One object of the present invention is to provide a vitamin E and C granule. The preparation is prepared by melt-extruding vitamin E, vitamin C and hydroxypropyl cellulose, thereby effectively improving the solubility of vitamin E and the stability of vitamin C.

[0006] Another object of the present invention is to provide a method for preparing vitamin E and C particles, which has a simple and easy preparation process, low cost, and can be adapted to large-scale production.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A vitamin E and C granule comprises 80-150 parts by weight of vitamin E, 160-300 parts by weight of vitamin C, 200-600 parts by weight of hydroxypropyl cellulose, and 1500-4000 parts by weight of an excipient, wherein the excipient is one or more of starch, dextrin, and sucrose.

[0009] Preferably, the excipients consist of starch, dextrin and sucrose.

[0010] Preferably, vitamin E is 90-120 parts by weight, vitamin C is 180-240 parts by weight, hydroxypropyl cellulose is 300-400 parts by weight, starch is 150-260 parts by weight, dextrin is 350-500 parts by weight, and sucrose is 1500-2400 parts by weight.

[0011] Preferably, the vitamin E is 100 parts by weight, the vitamin C is 200 parts by weight, the hydroxypropyl cellulose is 300 parts by weight, the starch is 200 parts by weight, the dextrin is 400 parts by weight, and the sucrose is 1800 parts by weight.

[0012] The vitamin E and C particles may further include one or more flavoring agents and coloring agents.

[0013] The flavoring agent is one or more sweeteners or flavors acceptable to the pharmaceutical industry, and the coloring agent is one or more pigments acceptable to the pharmaceutical industry.

[0014] The present invention also provides a method for preparing vitamin E and C particles, comprising the following steps:

[0015] (1) Mix vitamin E, vitamin C and hydroxypropyl cellulose, then preheat the hot melt extruder to 60~80℃, add the mixed vitamin E, vitamin C and hydroxypropyl cellulose into the hot melt extruder, melt and extrude them into strips.

[0016] (2) The strip-shaped extrudate is crushed and passed through an 80-mesh sieve, and then excipients and flavoring agents or colorants as needed are added and mixed. The mixture is then wet granulated, sized, and dried to obtain vitamin E and C granules.

[0017] Preferably, the hot melt extruder is preheated to 60-70°C.

[0018] Because the enediol group in the vitamin C structure is unstable, vitamin C is easily oxidized by air and loses its activity. In particular, contact with trace metal ions can increase its oxidation rate by tens of thousands of times. The present invention uses a hot melt extrusion method to coat vitamin C, thereby improving the stability of vitamin C and extending its storage time.

[0019] High temperature also accelerates the oxidation process of vitamin C. Generally, the acceleration doubles with every 10°C increase in temperature. After vitamin C is oxidized, its color gradually deepens, from almost colorless to light yellow, and then to yellow, yellowish brown, brownish red, and tan. In the preparation process of hot melt extrusion, high temperature is inevitably involved, which will also reduce the stability of vitamin C. During the process research, the applicant found that after vitamin E, vitamin C and hydroxypropyl cellulose are compounded, the temperature of hot melt extrusion can be significantly reduced. In addition to reducing energy consumption in the production process, it can also better protect vitamin C from oxidation, and the vitamin E after melt extrusion can significantly improve its hydrophilicity and promote its solubility in water, thereby solving the problem of vitamin E and C particles floating on the liquid surface and adsorbing on the cup wall when taking, resulting in loss of vitamin E dosage. DETAILED DESCRIPTION

[0020] In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the following examples are given for illustration. It should be noted that the following examples do not limit the scope of protection claimed by the present invention.

[0021] Unless otherwise specified, the raw materials, reagents, or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0022] Example 1

[0023] Weigh 100 g of vitamin E, 200 g of vitamin C, and 300 g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 70° C. Add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt them, extrude them into strips.

[0024] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve. 200 g of starch, 400 g of dextrin, and 1800 g of sucrose are added, and appropriate amounts of lemon yellow and orange essence are added and mixed. The mixture is then wet granulated. After granulation and drying, vitamin E and C granules are obtained.

[0025] Example 2

[0026] Weigh 80g of vitamin E, 160g of vitamin C, and 200g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 60°C, add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt and extrude them into strips.

[0027] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve. 150 g of starch, 350 g of dextrin, and 2400 g of sucrose are added, and appropriate amounts of lemon yellow and orange essence are added and mixed. The mixture is then wet granulated. After granulation and drying, vitamin E and C granules are obtained.

[0028] Example 3

[0029] Weigh 150 g of vitamin E, 300 g of vitamin C, and 600 g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 80° C. Add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt them, extrude them into strips.

[0030] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve. 260 g of starch, 500 g of dextrin, and 1500 g of sucrose are added, and appropriate amounts of lemon yellow and orange essence are added and mixed. The mixture is then wet granulated. After granulation and drying, vitamin E and C granules are obtained.

[0031] Example 4

[0032] Weigh 100 g of vitamin E, 200 g of vitamin C, and 400 g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 70° C. Add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt them, extrude them into strips.

[0033] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve. 1500 g of starch is added, and appropriate amounts of lemon yellow and orange essence are added and mixed. The mixture is then wet granulated. After granulation and drying, vitamin E and C granules are obtained.

[0034] Example 5

[0035] Weigh 100g of vitamin E, 200g of vitamin C, and 500g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 70°C, add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt and extrude them into strips.

[0036] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve, 4000 g of sucrose is added, and appropriate amounts of lemon yellow and orange essence are added and mixed, followed by wet granulation. After granulation and drying, vitamin E and C granules are obtained.

[0037] Comparative Example 1

[0038] Weigh 100g of vitamin E and 200g of vitamin C, add 300g of hydroxypropyl cellulose and mix well, then add 200g of starch, 400g of dextrin, 1800g of sucrose and appropriate amounts of lemon yellow and orange flavor, then wet granulate, granulate and dry to obtain vitamin E and C granules.

[0039] Comparative Example 2

[0040] Weigh 100 g of vitamin E, 200 g of vitamin C, and 300 g of hydroxypropyl cellulose and mix them evenly. Preheat the hot melt extruder to 90° C. Add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt them, extrude them into strips.

[0041] The strip-shaped extrudate is crushed and passed through an 80-mesh sieve. 200 g of starch, 400 g of dextrin, and 1800 g of sucrose are added, and appropriate amounts of lemon yellow and orange essence are added and mixed. The mixture is then wet granulated. After granulation and drying, vitamin E and C granules are obtained.

[0042] Comparative Example 3 Vitamin E and C granules produced by a certain company are commercially available.

[0043] Test Example 1

[0044] Stability test: Place the vitamin E and C granules at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%. Take samples at 0, 3, 6, 9, 12, 18, and 24 months, and then determine the vitamin E and vitamin C contents in accordance with the method for determining the content in the national drug standards of the State Food and Drug Administration (standard name: National Drug and Western Medicine Standard (Chemical Drug Local Standard Upgraded to National Standard Volume 13), standard number: WS-10001-(HD-1284)-2002).

[0045] Table 1 Vitamin E content results in the stability test of vitamin E and C granules

[0046] time 0 months 3 months 6 months 9 months 12 months 18 months 24 months Example 1 99.5% 100.1% 98.9% 99.1% 98.5% 99.3% 99.7% Example 2 100.6% 100.1% 99.8% 100.0% 98.9% 100.1% 98.8% Example 3 98.5% 99.1% 98.7% 97.9% 98.1% 97.8% 97.9% Example 4 101.2% 99.9% 100.8% 99.5% 100.2% 100.6% 100.3% Example 5 98.9% 98.6% 99.5% 100.1% 98.5% 98.7% 99.3% Comparative Example 1 100.5% 98.7% 95.5% 93.1% 91.5% 88.5% 86.1% Comparative Example 2 101.4% 97.3% 94.1% 91.6% 89.4% 84.1% 81.6% Comparative Example 3 98.7% 96.5% 95.1% 93.6% 92.1% 91.9% 90.1%

[0047] Table 2 Vitamin C content results in the stability test of vitamin E and C granules

[0048] time 0 months 3 months 6 months 9 months 12 months 18 months 24 months Example 1 100.3% 98.8% 99.6% 98.9% 99.8% 98.7% 99.7% Example 2 99.6% 98.1% 99.2% 98.7% 98.8% 99.1% 98.9% Example 3 100.1% 99.8% 99.1% 99.5% 99.3% 99.4% 99.3% Example 4 101.2% 99.8% 100.6% 100.9% 99.7% 99.9% 100.3% Example 5 100.8% 99.6% 100.1% 100.3% 99.6% 99.5% 100.4% Comparative Example 1 100.1% 97.2% 94.3% 92.8% 89.4% 87.7% 85.9% Comparative Example 2 98.9% 96.1% 92.9% 91.4% 88.3% 86.1% 84.7% Comparative Example 3 100.9% 98.0% 96.4% 95.0% 93.2% 92.0% 91.2%

[0049] Test Example 2

[0050] Solubility of vitamin E and C granules: Take 3g of vitamin E and C granules, add 100ml of water, and observe the dissolution of vitamin E and C granules.

[0051] Table 3 Vitamin E content results in the stability test of vitamin E and C granules

[0052] serial number Comparison of solubility measurement phenomena Example 1 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Example 2 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Example 3 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Example 4 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Example 5 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Comparative Example 1 All dissolved, slightly turbid at the bottom, oil droplets floating on the liquid surface, and oil droplets adsorbed on the wall of the cup Comparative Example 2 All dissolved, slightly turbid at the bottom, no oil floating on the liquid surface, no oil adsorbed on the wall of the cup Comparative Example 3 All dissolved, slightly turbid at the bottom, oil droplets floating on the liquid surface, and oil droplets adsorbed on the wall of the cup

[0053] Test Example 3

[0054] Dissolution (paddle method) test: Take vitamin E and C granules and perform in vitro dissolution test in different dissolution media according to the dissolution and release test method (paddle method) of the Chinese Pharmacopoeia 2020 edition.

[0055] (1) The dissolution medium was 900 ml of degassed purified water, the rotation speed was 50 r / min, and the temperature was 37.0℃±0.5℃. 5 ml of samples were taken after 5, 15, 30, 45, 60, and 120 min, respectively. The samples were filtered through a microporous filter membrane and an equal amount of medium was added. The filtrate was taken and measured by high performance liquid chromatography at a wavelength of 284 nm.

[0056] (2) The dissolution medium is 900 ml of degassed pH 1.2 hydrochloric acid medium, the rotation speed is 50 r / min, and the temperature is 37.0℃±0.5℃. Samples of 5 ml are taken after 5, 15, 30, 45, 60, and 120 minutes, respectively. The samples are filtered with a microporous filter membrane and an equal amount of medium is added. The filtrate is taken and measured by high performance liquid chromatography at a wavelength of 284 nm.

[0057] (3) The dissolution medium was 900 ml of degassed pH 4.5 acetate buffer, the rotation speed was 50 r / min, and the temperature was 37.0°C ± 0.5°C. 5 ml of samples were taken after 5, 15, 30, 45, 60, and 120 min, respectively. The samples were filtered through a microporous filter membrane and an equal amount of medium was added. The filtrate was taken and measured by high performance liquid chromatography at a wavelength of 284 nm.

[0058] (4) The dissolution medium was 900 ml of degassed pH 6.8 phosphate buffer, the rotation speed was 50 r / min, and the temperature was 37.0°C ± 0.5°C. 5 ml of samples were taken after 5, 15, 30, 45, 60, and 120 min, respectively. The samples were filtered through a microporous filter membrane and an equal amount of medium was added. The filtrate was taken and measured by high performance liquid chromatography at a wavelength of 284 nm.

[0059] Table 4 Vitamin C dissolution rate in in vitro dissolution test with purified water as dissolution medium (%)

[0060] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 84 69 73 79 81 78 89 83 10 95 92 94 96 93 96 95 94 15 97 95 98 98 98 98 97 97 30 98 99 97 98 97 97 98 99 45 98 97 99 97 96 98 98 97 60 97 98 98 98 98 97 99 98 120 98 99 98 97 99 98 98 99

[0061] Table 5 Vitamin E dissolution rate in in vitro dissolution test using purified water as dissolution medium (%)

[0062] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 49 55 61 57 54 1 2 2 10 67 70 72 66 71 3 2 4 15 86 88 84 85 87 5 3 5 30 94 95 93 96 95 3 4 3 45 96 97 98 98 97 3 5 5 60 99 98 97 99 98 5 4 6 120 98 98 99 99 99 3 4 4

[0063] Table 6 Vitamin C dissolution rate (%) in in vitro dissolution test using hydrochloric acid solution at pH 1.2

[0064] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 69 71 58 73 66 83 77 81 10 91 89 93 94 92 95 93 96 15 95 96 94 97 95 99 99 98 30 98 98 98 99 97 97 98 98 45 97 99 97 98 98 98 99 99 60 98 98 99 99 98 98 99 98 120 99 97 98 97 99 97 97 98

[0065] Table 7 Vitamin E dissolution rate (%) in the in vitro dissolution experiment using hydrochloric acid solution at pH 1.2

[0066] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 49 65 57 61 53 1 2 1 10 67 73 69 74 66 3 2 3 15 88 92 89 91 92 5 4 2 30 93 94 95 94 95 3 5 4 45 96 97 97 98 96 3 3 4 60 99 98 98 99 98 4 5 5 120 98 97 98 97 99 3 4 4

[0067] Table 8 Vitamin C dissolution rate (%) in in vitro dissolution experiment using acetate buffer at pH 4.5

[0068] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 84 71 78 82 69 78 69 73 10 95 93 95 97 91 96 94 95 15 97 98 97 99 96 98 97 98 30 98 98 98 98 98 97 99 98 45 98 99 99 98 97 98 97 98 60 97 98 98 97 99 97 98 97 120 98 99 97 98 98 98 99 98

[0069] Table 9 Vitamin E dissolution rate (%) in in vitro dissolution test using acetate buffer at pH 4.5

[0070] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 59 64 55 67 51 2 2 1 10 69 74 70 78 68 3 3 2 15 82 85 83 87 84 3 4 3 30 95 94 96 95 95 4 3 3 45 98 97 98 97 97 3 5 5 60 98 98 97 96 98 4 4 4 120 99 98 98 98 99 3 5 5

[0071] Table 10 Vitamin C dissolution rate (%) in in vitro dissolution test using pH 6.8 phosphate buffer as dissolution medium

[0072] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 2 5 85 81 88 76 83 87 85 78 10 97 95 96 95 95 95 94 96 15 97 98 98 97 98 99 98 97 30 99 99 98 98 99 97 99 98 45 98 98 97 98 98 98 97 98 60 97 99 99 99 97 98 99 97 120 98 98 98 97 98 97 98 98

[0073] Table 11 Vitamin E dissolution rate (%) in in vitro dissolution test using pH 6.8 phosphate buffer as dissolution medium

[0074] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 2 5 49 55 46 56 61 2 1 3 10 67 74 63 74 76 4 3 3 15 85 83 87 89 90 3 2 4 30 91 94 93 95 93 4 4 5 45 96 97 97 98 96 2 5 4 60 99 98 98 99 98 5 3 5 120 98 97 98 97 98 4 5 4

[0075] The results showed that compared with the comparative example, the dissolution performance of the highly water-soluble vitamin C in the examples did not differ significantly in dissolution media with different pH values, but the dissolution performance of the less water-soluble vitamin E in the examples did differ significantly in dissolution media with different pH values. The vitamin E prepared by hot-melt extrusion was rapidly released in different media, demonstrating a significant improvement in the water solubility of vitamin E. Rapid dissolution was achieved in dissolution media with different pH values, effectively improving bioavailability.

[0076] In summary, it can be seen that the hot melt extrusion method for preparing vitamin E and vitamin C composition particles can not only improve the hydrophilic properties of vitamin E, but also improve the phenomenon that vitamin E floats on the liquid surface when taken, thereby causing deviations in the dosage, while also improving the stability of vitamin C.

Claims

1. A vitamin E and C granule, characterized in that: The invention comprises 80-150 parts by weight of vitamin E, 160-300 parts by weight of vitamin C, 200-600 parts by weight of hydroxypropyl cellulose, and 1500-4000 parts by weight of an excipient; the excipient is one or more of starch, dextrin, and sucrose.

2. The vitamin E and C particles according to claim 1, wherein The excipient consists of starch, dextrin and sucrose.

3. The vitamin E and C particles according to claim 1, wherein The invention comprises 90 to 120 parts by weight of vitamin E, 180 to 240 parts by weight of vitamin C, 300 to 400 parts by weight of hydroxypropyl cellulose, 150 to 260 parts by weight of starch, 350 to 500 parts by weight of dextrin, and 1500 to 2400 parts by weight of sucrose.

4. The vitamin E and C particles according to claim 1, wherein The ingredients include 100 parts by weight of vitamin E, 200 parts by weight of vitamin C, 300 parts by weight of hydroxypropyl cellulose, 200 parts by weight of starch, 400 parts by weight of dextrin, and 1800 parts by weight of sucrose.

5. The vitamin E and C particles according to claim 1, wherein The vitamin E and C particles may further include one or more flavoring agents and coloring agents. The flavoring agents are one or more sweeteners or flavors acceptable to the pharmaceutical industry, and the coloring agents are one or more pigments acceptable to the pharmaceutical industry.

6. The method for preparing vitamin E and C particles according to claim 1, comprising the following steps: (1) Mix vitamin E, vitamin C, and hydroxypropyl cellulose, then preheat the hot melt extruder to 60-80°C, add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt and extrude them into strips; (2) The strip-shaped extrudate is crushed and passed through an 80-mesh sieve, and then excipients and flavoring agents or colorants as needed are added and mixed. The mixture is then wet granulated, sized, and dried to obtain vitamin E and C granules.

7. The method for preparing vitamin E and C particles according to claim 6, wherein: The hot melt extruder is preheated to 60-70°C.