Vitamin e, c granules and methods of making same

Abstract

The present application provides a kind of vitamin E, C granule and preparation method thereof, the vitamin E, C granule includes vitamin E 80~150 weight parts, vitamin C 160~300 weight parts, hydroxypropyl cellulose 200~600 weight parts, excipient 1500~4000 weight parts.The vitamin E of this application, vitamin C and hydroxypropyl cellulose are compounded, and vitamin E, C granule is prepared by using hot melt extrusion, can significantly reduce the temperature of hot melt extrusion, also can better protect vitamin C from oxidation, and the hydrophilicity of vitamin E after melt extrusion can be significantly improved, can promote the solubility in water, to solve the problem of vitamin E, C granule when taking, vitamin E floats on liquid surface or adsorbs on cup wall, and causes vitamin E dosage loss.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to vitamin E and C granules and a preparation method thereof. BACKGROUND

[0002] Vitamins are a kind of nutrients necessary for maintaining normal metabolism and functions of human bodies, and need to be obtained from the outside world as the human body cannot synthesize or cannot synthesize enough.

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

[0004] Vitamin E and vitamin C are both antioxidants, and the combination of the two can enhance the antioxidant effect, but vitamin C is easy to be oxidized by air and lose activity, and due to the difference in their own physicochemical properties, vitamin C is water-soluble and vitamin E is oil-soluble. The granules prepared by the conventional method are easy to cause vitamin E to float on the surface when washed with water, which is easy to adhere to the surface of the drinking container, resulting in the loss of vitamin E. Therefore, it is necessary to develop a granule product with simple preparation, convenient use and good stability. SUMMARY

[0005] One object of the present application is to provide a vitamin E and C granule, which effectively improves the solubility of vitamin E and the stability of vitamin C by melt-extruding vitamin E, vitamin C and hydroxypropyl cellulose.

[0006] Another object of the present application is to provide a preparation method of vitamin E and C granules, which is simple and easy to operate, low in cost and can adapt to large-scale production.

[0007] To achieve the above object, the present application adopts the following technical scheme:

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

[0009] Preferably, the excipient consists 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, vitamin E is 100 parts by weight, vitamin C is 200 parts by weight, hydroxypropyl cellulose is 300 parts by weight, starch is 200 parts by weight, dextrin is 400 parts by weight, and sucrose is 1800 parts by weight.

[0012] The vitamin E, C granule can further comprise one or more of a flavoring agent, a coloring agent.

[0013] The flavoring agent is one or more pharmaceutically acceptable sweeteners or essences, and the coloring agent is one or more pharmaceutically acceptable pigments.

[0014] The present application also provides a preparation method of the vitamin E, C granule, comprising the following steps:

[0015] (1) mixing vitamin E, vitamin C and hydroxypropyl cellulose, then preheating a hot melt extruder to 60-80°C, adding the mixed vitamin E, vitamin C and hydroxypropyl cellulose into the hot melt extruder, and extruding in a strip shape after melting and extruding.

[0016] (2) crushing the strip-shaped extrudate and passing it through an 80-mesh sieve, then adding an excipient and a flavoring agent or a coloring agent as needed, mixing, and then wet granulating, sizing, and drying to obtain the vitamin E, C granule.

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

[0018] Because the enediol group in the structure of vitamin C is unstable, vitamin C is easily oxidized by air and loses activity, especially when it comes into contact with trace metal ions, which can increase the oxidation rate by tens of thousands of times. The present application uses a hot melt extrusion method to coat vitamin C, improve the stability of vitamin C, and prolong its storage time.

[0019] High temperature also has an accelerating effect on the oxidation process of vitamin C, and generally the accelerating effect doubles with every 10℃ increase in temperature. After vitamin C is oxidized, the color gradually darkens, from almost colorless to light yellow, then to yellow, yellow-brown, brown red, and brown. In the preparation of hot melt extrusion, high temperature is inevitably involved, which also reduces 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, which can not only reduce the energy consumption in the production process, but also better protect vitamin C from oxidation, and after melt extrusion, vitamin E can significantly improve the hydrophilicity and promote the solubility in water, thereby solving the problem of vitamin E dosage loss caused by floating on the liquid surface and adsorbing on the cup wall during taking. DETAILED DESCRIPTION

[0020] In order to make the skilled in the art more clearly understand the technical solutions described in the present application, the following examples are given for illustration. It should be pointed out that the following examples do not constitute a limitation on the scope of protection required by the present application.

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

[0022] Example 1

[0023] Take 100g of vitamin E, 200g of vitamin C and 300g of hydroxypropyl cellulose, mix them evenly, preheat the hot melt extruder to 70℃, then add the mixed vitamin E, vitamin C and hydroxypropyl cellulose into the hot melt extruder, and extrude in strip shape after melting and extruding.

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

[0025] Example 2

[0026] Take 80g of vitamin E, 160g of vitamin C and 200g of hydroxypropyl cellulose, mix them evenly, preheat the hot melt extruder to 60℃, then add the mixed vitamin E, vitamin C and hydroxypropyl cellulose into the hot melt extruder, and extrude in strip shape after melting and extruding.

[0027] The strip-shaped extrudate is crushed and sieved through an 80-mesh screen, 150 g of starch, 350 g of dextrin, 2400 g of sucrose, and an appropriate amount of lemon yellow and orange flavor are added and mixed, and then wet granulation is performed, and the granules are dried to obtain vitamin E and C granules.

[0028] Example 3

[0029] Vitamin E 150 g, vitamin C 300 g, and hydroxypropyl cellulose 600 g are mixed uniformly, the hot melt extruder is preheated to 80°C, the mixed vitamin E, vitamin C, and hydroxypropyl cellulose are added to the hot melt extruder, and then melting and extrusion are performed to obtain a strip-shaped extrudate.

[0030] The strip-shaped extrudate is crushed and sieved through an 80-mesh screen, 260 g of starch, 500 g of dextrin, and 1500 g of sucrose are added and mixed, and then wet granulation is performed, and the granules are dried to obtain vitamin E and C granules.

[0031] Example 4

[0032] Vitamin E 100 g, vitamin C 200 g, and hydroxypropyl cellulose 400 g are mixed uniformly, the hot melt extruder is preheated to 70°C, the mixed vitamin E, vitamin C, and hydroxypropyl cellulose are added to the hot melt extruder, and then melting and extrusion are performed to obtain a strip-shaped extrudate.

[0033] The strip-shaped extrudate is crushed and sieved through an 80-mesh screen, 1500 g of sucrose is added and mixed, and then wet granulation is performed, and the granules are dried to obtain vitamin E and C granules.

[0034] Example 5

[0035] Vitamin E 100 g, vitamin C 200 g, and hydroxypropyl cellulose 500 g are mixed uniformly, the hot melt extruder is preheated to 70°C, the mixed vitamin E, vitamin C, and hydroxypropyl cellulose are added to the hot melt extruder, and then melting and extrusion are performed to obtain a strip-shaped extrudate.

[0036] The strip-shaped extrudate is crushed and sieved through an 80-mesh screen, 4000 g of sucrose is added and mixed, and then wet granulation is performed, and the granules are dried to obtain vitamin E and C granules.

[0037] Comparative Example 1

[0038] Vitamin E 100 g and vitamin C 200 g are mixed uniformly, 300 g of hydroxypropyl cellulose is added, 200 g of starch, 400 g of dextrin, 1800 g of sucrose, and an appropriate amount of lemon yellow and orange flavor are added, and then wet granulation, granulation, and drying are performed to obtain vitamin E and C granules.

[0039] Comparative Example 2

[0040] Take 100 g of vitamin E, 200 g of vitamin C, and 300 g of hydroxypropyl cellulose, mix them well, and then preheat the hot melt extruder to 90°C. Add the mixed vitamin E, vitamin C, and hydroxypropyl cellulose into the hot melt extruder, melt and extrude them in a strip shape.

[0041] After crushing the strip-shaped extrudate through an 80-mesh sieve, add 200 g of starch, 400 g of dextrin, and 1800 g of sucrose, and then add an appropriate amount of lemon yellow and orange flavoring. Mix them well, and then perform wet granulation. After sizing and drying, the vitamin E and C granules are obtained.

[0042] Comparative Example 3

[0043] Test Example 1

[0044] Stability Test: Take the vitamin E and C granules and place them in a temperature of 25°C±2°C and a relative humidity of 60%±5%. Take samples at 0 months, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months, respectively, and then determine the content of vitamin E and vitamin C according to the method for content determination in the National Drug Standard (Standard Name: National Drug Standard for Western Medicine (Chemical Medicine), Standard Number: WS-10001-(HD-1284)-2002) issued by the National Drug Administration of China.

[0045] Table 1: Results of Vitamin E Content in the Stability Test of Vitamin E and C Granules

[0046] Time 0 month 3 month 6 month 9 month 12 month 18 month 24 month 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: Results of Vitamin C Content in the Stability Test of Vitamin E and C Granules

[0048] Time 0 month 3 month 6 month 9 month 12 month 18 month 24 month 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] Dissolution of Vitamin E and C Granules: Take 3 g of vitamin E and C granules and add them to 100 ml of water. Observe the dissolution of the vitamin E and C granules.

[0051] Table 3: Results of Vitamin E Content in the Stability Test of Vitamin E and C Granules

[0052] No. Dissolution test phenomenon Example 1 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Example 2 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Example 3 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Example 4 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Example 5 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Comparative Example 1 All dissolved, slight turbidity at the bottom, oil floating on the liquid surface, oil adsorbed on the cup wall Comparative Example 2 All dissolved, slight turbidity at the bottom, no oil floating on the liquid surface, no oil adsorbed on the cup wall Comparative Example 3 All dissolved, slight turbidity at the bottom, oil floating on the liquid surface, oil adsorbed on the cup wall

[0053] Test Example 3

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

[0055] (1) The dissolution medium is degassed purified water 900 ml, the rotation speed is 50 r / min, the temperature is 37.0℃±0.5℃, and 5 ml of sample is taken at 5, 15, 30, 45, 60 and 120 min, respectively, filtered with a microporous filter, and supplemented with an equal amount of medium. Take the filtrate, and determine at a wavelength of 284 nm using high performance liquid chromatography.

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

[0057] (3) The dissolution medium is degassed pH 4.5 acetic acid buffer 900 ml, the rotation speed is 50 r / min, the temperature is 37.0℃±0.5℃, and 5 ml of sample is taken at 5, 15, 30, 45, 60 and 120 min, respectively, filtered with a microporous filter, and supplemented with an equal amount of medium. Take the filtrate, and determine at a wavelength of 284 nm using high performance liquid chromatography.

[0058] (4) The dissolution medium is degassed pH 6.8 phosphate buffer 900 ml, the rotation speed is 50 r / min, the temperature is 37.0℃±0.5℃, and 5 ml of sample is taken at 5, 15, 30, 45, 60 and 120 min, respectively, filtered with a microporous filter, and supplemented with an equal amount of medium. Take the filtrate, and determine at a wavelength of 284 nm using high performance liquid chromatography.

[0059] Table 4 In vitro dissolution test of vitamin C in purified water as the 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 In vitro dissolution test of vitamin E in purified water as the 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 In vitro dissolution test of vitamin C in pH 1.2 hydrochloric acid solution as the dissolution medium

[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 in-vitro dissolution experiment with pH 1.2 hydrochloric acid as dissolution medium

[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 with pH 4.5 acetate buffer as dissolution medium

[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 experiment with pH 4.5 acetate buffer as dissolution medium

[0070] Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 2 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 experiment with 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 experiment with 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 Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 2 Time (min) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 2 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 show that, compared with the comparative examples, the dissolution performance of the vitamin C composition with good water solubility in different pH value dissolution medium has no obvious difference, but the dissolution performance of the vitamin E composition with poor water solubility in different pH value dissolution medium has obvious difference. The vitamin E prepared by the hot melt extrusion method can be quickly released in different media, which shows that the water solubility of vitamin E has been obviously improved. In different pH value dissolution medium, it can achieve fast dissolution, which can effectively improve the bioavailability.

[0076] In summary, it can be seen that the vitamin E and vitamin C composition particles prepared by the hot melt extrusion method can improve the hydrophilic property of vitamin E, improve the phenomenon that the floating liquid surface of vitamin E during taking causes the dosage deviation, and also improve the stability of vitamin C.

Claims

1. A vitamin E, C granule, characterized by, The vitamin E 80~150 parts by weight, vitamin C 160~300 parts by weight, hydroxypropyl cellulose 200~600 parts by weight, excipient 1500~4000 parts by weight; the excipient is one or more of starch, dextrin, sucrose; the preparation method of the vitamin E, C granules comprises the following steps: (1) the vitamin E, vitamin C, hydroxypropyl cellulose is mixed, then the hot melt extruder is preheated to 60~80℃, the mixed vitamin E, vitamin C, hydroxypropyl cellulose is added to the hot melt extruder, and is extruded in strip shape after melting; (2) the strip-shaped extrudate is crushed and then sieved through 80 mesh, then the excipient and the flavoring agent or the colorant added according to the need are mixed, then wet granulation, whole granulation and drying are carried out, and the vitamin E, C granules are obtained.

2. The vitamin E, C granules according to claim 1, wherein The excipient is composed of starch, dextrin and sucrose.

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

4. The vitamin E, C granules of claim 1, wherein, 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.

5. The vitamin E, C granules of claim 1, wherein the vitamin E is present in an amount of about 0.1 to 10% by weight of the granules. The vitamin E, C granules can also comprise one or more of a flavoring agent and a colorant, wherein the flavoring agent is one or more pharmaceutically acceptable sweeteners or essences, and the colorant is one or more pharmaceutically acceptable pigments.

6. The vitamin E, C granules of claim 1, wherein, The hot melt extruder is preheated to 60~70℃.