JP2024012181A - Choline-containing composition of various vitamins and minerals as well as preparation method and application thereof - Google Patents

Abstract

To provide a composition of various vitamins and minerals having solved problems such as moisture absorption and browning.SOLUTION: The present application relates to a choline-containing composition of various vitamins and minerals as well as a preparation method and application thereof. According to the method, the hygroscopicity of choline bitartrate is improved, the cracking and swelling phenomena of the prepared tablets are obviously improved, and a colored coating containing synthetic pigments does not need to be used for covering potential browning of the tablets. After transparent coating is conducted, after three-month accelerated stability investigation is conducted under the conditions of 37°C and 75% of relative humidity, the nutrient content is stable, and the appearance is perfect.SELECTED DRAWING: Figure 1

Description

This application is based on and claims priority to CN application number 202210826070.7, filing date July 14, 2022. The disclosure of this CN application is incorporated into this application in its entirety.

TECHNICAL FIELD The present application relates to the technical field of formulations or health foods, and in particular to compositions, especially choline-containing compositions of multiple vitamins and minerals, processes for their preparation and uses thereof.

Vitamins are a type of trace organic substances necessary for the human body to maintain normal physiological functions, and include vitamin A, vitamin C, and B group vitamins. Minerals are a general term for various inorganic substances that constitute human tissues and maintain normal physiological functions, such as macro elements such as calcium and magnesium, and trace elements such as iron, zinc, and selenium. Vitamins and minerals play important roles in the growth, metabolism, and development of the human body, but most of them cannot be synthesized by the human body and must be obtained from food. Nutraceuticals containing multiple vitamins and minerals in tablet form can also be used when people are not getting enough nutrients from food.

However, the system of multiple vitamin and mineral tablets is complex, and after moisture absorption, the ingredients are likely to react with each other and cause browning, especially if vitamins and choline are added. Choline is an organic base and is the main component of lecithin and sphingomyelin, which can ensure the development of the brain and nervous system and promote fat metabolism in the liver. Among the multiple vitamin and mineral tablets on the market, only a handful contain choline. Two common choline sources, choline bitartrate and choline chloride, are white crystalline powders that easily absorb moisture and require large amounts to be added, making them difficult to use in manufacturing processes. Currently, the appearance of several vitamin and mineral tablets on the market is often modified by colored coatings, but although colored coatings can hide the brown color of tablets after moisture absorption, cannot hide damage to the coating after it swells.

Content of the Invention In order to solve the problems existing in the prior art, the present application discloses a tablet containing multiple vitamins and minerals. The tablet has a beautiful appearance and only requires a clear coating. The nutrient content remains stable even after accelerated stability testing for one month at 37° C. and 75% relative humidity. The present application further discloses a process for manufacturing tablets that effectively solves the problems of swelling, splitting and browning of tablets containing multiple vitamins and minerals.

Specifically, in one aspect, the present application provides a composition comprising vitamins, choline and minerals, which composition comprises the following ingredients:
Ingredient 1: Choline bitartrate;
Ingredient 2: The following nutrients: Minerals including calcium, magnesium, iron, zinc, and selenium;
Ingredient 3: Vitamins including the following nutrients: vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, pantothenic acid, vitamin B ₂ , vitamin B ₁₂ , and folic acid;
Ingredient 4: Ascorbyl palmitate.

In some embodiments, the choline bitartrate is present in the form of a separate dosage unit, eg, in the form of microcapsules. In some embodiments, in addition to choline bitartrate, the microcapsules further include a filler and an encapsulant. In some embodiments, the filler is selected from the group consisting of corn starch, microcrystalline cellulose, dextrin (eg, maltodextrin). In some embodiments, the encapsulant material is selected from the group consisting of ethylcellulose, cellulose acetate, and hydroxypropylcellulose.

In some embodiments, the mineral is present in the form of a separate dosage unit, such as mineral granules. In some embodiments, in addition to nutrients, the mineral granules further include a binding agent. In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, povidone, copovidone, and gelatin.

In some embodiments, component 3 does not include vitamin C.

In some embodiments, the components included in component 3 are divided into two groups:

Group 1: vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid;
Group 2: vitamin _B2 , vitamin _B12 , and folic acid;
The first group further includes a filler, and the first group further includes a lubricant.

In some embodiments, the filler is selected from the group consisting of starch, microcrystalline cellulose, dextrin, and maltodextrin.

In some embodiments, the first group further includes one or more selected from the group consisting of microcrystalline cellulose, maltodextrin, copovidone, starch, and croscarmellose sodium. In some embodiments, the lubricant is selected from the group consisting of silicon dioxide, magnesium stearate, talcum powder, and micronized silica gel. In some embodiments, the first group and the second group are mixed separately and then combined.

In some embodiments, the content of each nutrient in the composition, in weight percent, is as follows:
0.16-0.80 parts vitamin A, 0.002-0.015 parts vitamin D, 5-150 parts vitamin E, 0.015-0.10 parts vitamin K, 0.5-20 parts of vitamin B ₁ , 0.5-20 parts of vitamin B ₂ , 0.5-10 parts of vitamin B ₆ , 0.0005-0.01 parts of vitamin B ₁₂ , 3-15 parts of niacin, 0.08 ~0.50 parts folic acid, 0.01-0.10 parts biotin, 1-20 parts pantothenic acid, 30-500 parts vitamin C, 100-1000 parts choline, 200-1000 parts calcium, 65 ~350 parts magnesium, 5-20 parts iron, 3-15 parts zinc, 10-100 parts selenium,
The raw material that provides vitamin C is ascorbyl palmitate;
The raw material that supplies choline is choline bitartrate.

In some embodiments, the composition is a tablet or capsule.

In some embodiments, based on 2000 tablets/capsules, the composition includes the following nutrients:
80-400 mg vitamin A, 1-7.5 mg vitamin D, 2.5-75 g vitamin E, 7.5-50 mg vitamin K, 0.25-10 g vitamin B ₁ , 0.25-10 g Vitamin B ₂ , 0.25-5g vitamin B ₆ , 0.25-5mg vitamin B ₁₂ , 1.5-7.5g niacin, 40-250mg folic acid, 5-50mg biotin, 0.5-5g 10g pantothenic acid, 15-250g vitamin C, 50-500g choline, 100-500g calcium, 32.5-175g magnesium, 2.5-10g iron, 1.5-7.5g zinc, 5 ~50g of selenium.

In another aspect, the application provides a method for preparing a composition according to any one of claims 1 to 6, comprising the steps of:
(1) Prepare choline bitartrate microcapsules;
(2) Preparation of mineral granules: mix raw materials supplying calcium, magnesium, iron, and zinc and granulate to obtain mineral granules;
(3) Preparation of vitamin premix: Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid are mixed uniformly to obtain vitamin premix 1; _B2 , vitamin _B12 , and folic acid are uniformly mixed to obtain vitamin premix 2; vitamin premix 1 and vitamin premix 2 are uniformly mixed to obtain vitamin premix;
(4) Formulation: mix choline bitartrate microcapsules, mineral granules, vitamin premix and ascorbyl palmitate to obtain a mixed material, then formulate to obtain the required dosage form;
Optionally, further comprising the step of coating the dosage form obtained in step (4).

In some embodiments, the selenium-providing ingredient is mixed with the calcium, magnesium, iron, and zinc-providing ingredient in step (2) or mixed with the ingredients of vitamin premix 1 in step (3). be done.

The amount of each nutrient added in the present invention is within the appropriate range required by the human body, and the raw materials for supplying each nutrient are known to those skilled in the art, and those skilled in the art will be able to do so based on their general technical knowledge. can be selected. More specifically, raw materials for supplying calcium include calcium carbonate, calcium acetate, calcium chloride, calcium citrate, calcium gluconate, calcium lactate, calcium hydrogen phosphate, calcium dihydrogen phosphate, and tricalcium phosphate ( Calcium phosphate), calcium sulfate, calcium L-lactate, calcium glycerophosphate, calcium citrate malate, and the like. Examples of raw materials for supplying magnesium include magnesium carbonate, magnesium sulfate, magnesium oxide, magnesium chloride, magnesium L-threonate, and magnesium gluconate. Raw materials that supply iron include ferrous gluconate, ferrous fumarate, ferrous sulfate, ferrous lactate, ferrous succinate, ferric pyrophosphate, ferric citrate, and citric acid. Examples include ferrous sodium. Examples of raw materials for supplying zinc include zinc sulfate, zinc citrate, zinc citrate (trihydrate), zinc gluconate, zinc oxide, zinc lactate, zinc acetate, and zinc chloride. Examples of raw materials for supplying selenium include sodium selenite, selenium-enriched yeast, L-selenium-methylselenocysteine, selenocarrageenan, selenoprotein, and sodium selenate. Raw materials that supply vitamin A include retinyl acetate, retinyl palmitate, β-carotene, and the like. Examples of raw materials for supplying vitamin _B1 include thiamine hydrochloride and thiamine nitrate. Raw materials that supply vitamin _B2 include riboflavin, riboflavin-5'-sodium phosphate, and the like. Examples of raw materials for supplying vitamin _B6 include pyridoxine hydrochloride. Examples of raw materials that supply vitamin _B12 include cyanocobalamin. Raw materials for supplying niacin include nicotinic acid, nicotinamide, and the like. Examples of raw materials for supplying pantothenic acid include calcium D-pantothenate and sodium D-pantothenate. Raw materials that supply vitamin E include D-α-tocopherol, D-α-tocopherol acetate, D-α-tocopherol succinate, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and vitamin E calcium. Can be mentioned. Examples of raw materials for supplying vitamin K include vitamin K ₁ and vitamin K ₂ . Examples of raw materials for supplying vitamin D include vitamin D ₂ and vitamin D ₃ . D-biotin can be mentioned as a raw material for supplying biotin.

In some embodiments, choline bitartrate microcapsules are prepared by the following steps:
a) Mix choline bitartrate and filler uniformly;
b) uniformly mix the capsule material to obtain a coating solution;
c) The products obtained in steps a) and b) are mixed homogeneously and dried to obtain choline bitartrate microcapsules.

In some embodiments, drying is performed in a spray dryer and fluidized bed, respectively.

In some embodiments, a sieving operation is further included after drying.

In some embodiments, the filler and encapsulant are as defined above.

In some embodiments, in step (2), a binder is added to the mixed feedstock and granulation (eg, boil granulation) is performed.

In some embodiments, the binding agent is as defined in any one of the preceding items.

In some embodiments, adding fillers to the vitamins is also included during the preparation of Vitamin Premix 1.

In some embodiments, adding a lubricant to the vitamins during the preparation of Vitamin Premix 2 is also included.

In some embodiments, fillers and lubricants are as defined in any one of the preceding items.

In some embodiments, in step (4), the mixed material further includes one or more of a filler, a binder, and a disintegrant.

In some embodiments, the filler is selected from the group consisting of starch, microcrystalline cellulose, and dextrin (eg, maltodextrin).

In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, povidone, copovidone, and gelatin.

In some embodiments, the disintegrant is croscarmellose sodium.

In another aspect, the application provides the use of a composition according to any one of the items of the first aspect in the manufacture of a dietary supplement.

Beneficial Effects of the Invention The present application provides a choline-containing composition of multiple vitamins and minerals, as well as methods of preparation and uses thereof, which are able to achieve at least one of the following technical effects:
1. The hygroscopicity of choline bitartrate is improved;
2. The composition slows or prevents the complexation reaction of vitamin C while retaining the antioxidant capacity of vitamin C;
3. Since the tablets prepared by the method of the present invention can adopt a transparent coating, their appearance is beautiful and the problems of browning, tablet breakage and swelling are significantly improved.

The accompanying drawings described herein are used to provide a further understanding of the invention, and form a part of this application. The schematic examples of the invention and the description thereof are used to explain the invention and do not constitute an undue limitation of the invention. In the attached drawings:
FIG. 1 shows the changes observed in the tablets prepared in Examples 1 to 4 under conditions of 37° C. and 75% RH for one day. FIG. 2 shows the changes observed in the tablets prepared in Comparative Examples 1 to 4 under conditions of 37° C. and 75% RH for one day. FIG. 3 shows the weight increase observed for the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 under conditions of 37° C. and 75% RH for one day.

Specific Model for Carrying Out the Invention Hereinafter, embodiments of the present invention will be described in detail together with examples. Those skilled in the art will understand that they are not to be considered as limiting the scope. Where there are no specific conditions in the examples, they are carried out according to conventional conditions or conditions suggested by the manufacturer. Additionally, all reagents and equipment used that were not specified by the manufacturer were conventional commercially available products.

Example 1
Formulation 1 (1700g, 2000 tablets):
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B ₁ 3g, Vitamin B ₂ 3g, Vitamin B ₆ 3g, Vitamin B ₁₂ 3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 110g.

The preparation process was as follows:
(1) Preparation of choline bitartrate microcapsules 1) Grind 1 kg choline bitartrate, sieve, add 50 g corn starch and mix well for later use;
2) Weighed 50 g of ethyl cellulose and 3 g of silicon dioxide in proportion and dissolved them with a high-speed homogenizer to obtain a coating solution for later use;
3) The choline bitartrate and cornstarch mixture from step 1) was mixed with the coating solution from step 2) and homogenized with a high speed homogenizer;
4) After spray drying the mixture in step 3) with a spray dryer, it was transferred to a fluidized bed and dried to obtain choline bitartrate microcapsules;
5) Choline bitartrate microcapsules were sieved and stored in a dry environment.

(2) Preparation of mineral granules Calcium carbonate, ferrous fumarate, zinc gluconate, and magnesium carbonate were taken according to the prescribed amounts, added to a fluidized bed, and boiled granulated using 3% hydroxypropyl methylcellulose solution as a binder. Ta. After granulation, the obtained mineral granules were sieved for later use.

(3) Preparation of vitamin premix Take vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, pantothenic acid, and selenium-enriched yeast according to the prescribed amounts, and add the same amount of microcrystals. Mixed uniformly with cellulose. Vitamin B ₂ , vitamin B ₁₂ , folic acid, and silicon dioxide were taken according to the prescribed amounts and mixed uniformly with the above vitamin mixture to obtain a vitamin premix.

(4) Blending and tabletting Mineral granules, vitamin premix, choline bitartrate microcapsules, ascorbyl palmitate (for vitamin C supplementation), microcrystalline cellulose, maltodextrin, copovidone, starch, croscarmellose sodium, magnesium stearate. One or more types were taken according to the prescribed amount, blended together, and then subjected to tableting;

(5) Coating An appropriate amount of a transparent coating agent was taken and dissolved in an appropriate amount of water so that the mass fraction of the coating agent was 10%. After preheating the coating pan, place uncoated tablets into the coating pan and control the following conditions: inlet air temperature 70 ± 10 °C, tablet bed temperature 50 ± 5 °C, outlet air temperature 55 ± 10 °C, and injection pressure 0.4 MPa. Then, the coating liquid was sprayed onto the tablet surface to form a film, thereby obtaining a coated tablet.

Example 2
Prescription 2 (1700g, 2000 tablets)
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 12.5g, Selenium 80mg, Vitamin A 358mg, Vitamin D 10mg, Vitamin E 25g, Vitamin K 80mg, Vitamin B ₁ 3.5g, Vitamin B ₂ 3.5g, Vitamin B ₆ 3.5g, vitamin _B12 5mg, niacin 12g, folic acid 300mg, biotin 50mg, pantothenic acid 5g, vitamin C 50g, choline bitartrate 120g. The preparation process was similar to Example 1.

Example 3
Formulation 3 (1700g, 2000 tablets)
Calcium 300g, Magnesium 70g, Iron 16g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B _1.3g , Vitamin B _2.3g , Vitamin B _6.3g , Vitamin B _12.3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 120g. The preparation process was similar to Example 1.

Example 4
Formulation 4 (1700g, 2000 tablets)
Calcium 300g, Magnesium 70g, Iron 10g, Zinc 2.8g, Selenium 26mg, Vitamin A 160mg, Vitamin D 8mg, Vitamin E 12g, Vitamin K 20mg, Vitamin B ₁ 1.6g, Vitamin B ₂ 3.5g, Vitamin B ₆ 1.6g, vitamin B ₁₂ 1.6mg, niacin 3.2g, folic acid 400mg, biotin 26mg, pantothenic acid 1.26g, vitamin C 50g, choline bitartrate 120g. The preparation process was similar to Example 1.

Comparative example 1
Comparative formulation 1 (1700g, 2000 tablets)
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B ₁ 3g, Vitamin B ₂ 3g, Vitamin B ₆ 3g, Vitamin B ₁₂ 3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 110g.

(1) Preparation of mineral granules Calcium carbonate, ferrous fumarate, zinc gluconate, magnesium carbonate, selenium-enriched yeast were taken according to the prescribed amounts, added to a fluidized bed dryer, and 3% hydroxypropyl methylcellulose solution was added as a binder. Boiling granulation was performed as follows. After granulation, the obtained mineral granules were sieved for later use.

(2) Preparation of vitamin premix Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid are taken according to the prescribed amounts and mixed uniformly with the same amount of microcrystalline cellulose. did. Vitamin B ₂ , vitamin B ₁₂ , and folic acid were taken according to prescribed amounts, mixed uniformly with silicon dioxide, and then uniformly mixed with the vitamin mixture described above to obtain a vitamin premix.

(3) Blending and tabletting Mineral granules, vitamin premix, commercially available choline bitartrate, commercially available ascorbic acid, microcrystalline cellulose, and magnesium stearate were taken according to the prescribed amounts, blended together, and then compressed into tablets;

(4) Coating An appropriate amount of a transparent coating agent was taken and dissolved in an appropriate amount of water so that the mass fraction of the coating agent was 10%. After preheating the coating pan, place uncoated tablets into the coating pan and control the following conditions: inlet air temperature 70 ± 10 °C, tablet bed temperature 50 ± 5 °C, outlet air temperature 55 ± 10 °C, and injection pressure 0.4 MPa. Then, the coating liquid was sprayed onto the tablet surface to form a film, thereby obtaining a coated tablet.

Comparative example 2
Comparative formulation 2 (1700g, 2000 tablets)
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B ₁ 3g, Vitamin B ₂ 3g, Vitamin B ₆ 3g, Vitamin B ₁₂ 3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 110g.

(1) Preparation of mineral particles Calcium carbonate, ferrous fumarate, zinc gluconate, magnesium carbonate, and selenium-enriched yeast were taken according to the prescribed amounts, added to a fluidized bed dryer, and combined with 3% hydroxypropyl methylcellulose solution. Boiling granulation was performed as an agent. After granulation, the mineral granules obtained were sieved for later use.

(2) Preparation of vitamin premix Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid are taken according to the prescribed amounts and mixed uniformly with the same amount of microcrystalline cellulose. did. Vitamin B ₂ , vitamin B ₁₂ , and folic acid were taken according to prescribed amounts, mixed uniformly with silicon dioxide, and then mixed with the previous vitamin mixture to obtain a vitamin premix.

(3) Blending and tableting Mineral granules, vitamin premix, commercially available choline bitartrate, ascorbyl palmitate, microcrystalline cellulose, and magnesium stearate were taken according to the prescribed amounts, blended together, and then compressed into tablets;

(4) Coating An appropriate amount of a transparent coating agent was taken and dissolved in an appropriate amount of water so that the mass fraction of the coating agent was 10%. After preheating the coating pan, place uncoated tablets into the coating pan and control the following conditions: inlet air temperature 70 ± 10 °C, tablet bed temperature 50 ± 5 °C, outlet air temperature 55 ± 10 °C, and injection pressure 0.4 MPa. Then, the coating liquid was sprayed onto the tablet surface to form a film, thereby obtaining a coated tablet.

Comparative example 3
Comparative formulation 3 (1700g, 2000 tablets)
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B ₁ 3g, Vitamin B ₂ 3g, Vitamin B ₆ 3g, Vitamin B ₁₂ 3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 110g.

(1) Preparation of choline bitartrate microcapsules 1) Grind 1 kg choline bitartrate, sieve, add 50 g corn starch and mix well for later use;
2) Weighed the proportion of 50 g of ethyl cellulose and 3 g of silicon dioxide and dissolved it with a high-speed homogenizer to obtain a coating solution for later use;
3) The choline bitartrate and cornstarch mixture from step 1) was mixed with the coating solution from step 2) and homogenized with a high speed homogenizer;
4) After spray drying the mixture in step 3) with a spray dryer, it was transferred to a fluidized bed and dried to obtain choline bitartrate microcapsules;
5) Choline bitartrate microcapsules were sieved and stored in a dry environment.

(2) Preparation of mineral granules Calcium carbonate, ferrous fumarate, zinc gluconate, magnesium carbonate, and selenium-enriched yeast were taken according to the prescribed amounts, added to a fluidized bed dryer, and combined with 3% hydroxypropyl methylcellulose solution. Boiling granulation was performed as an agent. After granulation, the mineral granules obtained were sieved for later use.

(3) Preparation of vitamin premix Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid are taken according to the prescribed amounts and mixed uniformly with the same amount of microcrystalline cellulose. did. Vitamin B ₂ , vitamin B ₁₂ , folic acid, and silicon dioxide were taken according to prescribed amounts, mixed uniformly, and then uniformly mixed with the previous vitamin mixture to obtain a vitamin premix.

(4) Blending and tabletting Mineral granules, vitamin premix, choline bitartrate microcapsules, commercially available ascorbic acid, microcrystalline cellulose, and magnesium stearate were taken according to the prescribed amounts, blended together, and then compressed into tablets;

(5) Coating An appropriate amount of a transparent coating agent was taken and dissolved in an appropriate amount of water so that the mass fraction of the coating agent was 10%. After preheating the coating pan, place uncoated tablets into the coating pan and control the following conditions: inlet air temperature 70 ± 10 °C, tablet bed temperature 50 ± 5 °C, outlet air temperature 55 ± 10 °C, and injection pressure 0.4 MPa. Then, the coating liquid was sprayed onto the tablet surface to form a film, thereby obtaining a coated tablet.

Comparative example 4
Comparative formulation 4 (1700g, 2000 tablets)
Calcium 240g, Magnesium 70g, Iron 7g, Zinc 8g, Selenium 26mg, Vitamin A 340mg, Vitamin D 8mg, Vitamin E 10g, Vitamin K 45mg, Vitamin B ₁ 3g, Vitamin B ₂ 3g, Vitamin B ₆ 3g, Vitamin B ₁₂ 3mg , niacin 10g, folic acid 300mg, biotin 42mg, pantothenic acid 6g, vitamin C 50g, choline bitartrate 110g.

(1) Preparation of choline bitartrate microcapsules 1) Grind 1 kg choline bitartrate, sieve, add 50 g corn starch and mix well for later use;
2) Weighed the proportion of 50 g of ethyl cellulose and 3 g of silicon dioxide and dissolved it with a high-speed homogenizer to obtain a coating solution for later use;
3) The choline bitartrate and cornstarch mixture from step 1) was mixed with the coating solution from step 2) and homogenized with a high speed homogenizer;
4) After spray drying the mixture in step 3) with a spray dryer, it was transferred to a fluidized bed and dried to obtain choline bitartrate microcapsules;
5) Choline bitartrate microcapsules were sieved and stored in a dry environment.

(2) Preparation of mineral granules Calcium carbonate, ferrous fumarate, zinc gluconate, magnesium carbonate, and selenium-enriched yeast were taken according to the prescribed amounts, added to a fluidized bed dryer, and combined with 3% hydroxypropyl methylcellulose solution. Boiling granulation was performed as an agent. After granulation, the mineral granules obtained were sieved for later use.

(3) Preparation of vitamin premix Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, pantothenic acid, vitamin B ₂ , vitamin B ₁₂ , and folic acid are taken according to the prescribed amounts. , mixed in a three-dimensional mixer for later use.

(4) Blending and tabletting Mineral granules, vitamin premix, choline bitartrate microcapsules, ascorbyl palmitate, microcrystalline cellulose, and magnesium stearate were taken according to the prescribed amounts, blended together, and then compressed into tablets;

(5) Coating An appropriate amount of a transparent coating agent was taken and dissolved in an appropriate amount of water so that the mass fraction of the coating agent was 10%. After preheating the coating pan, place uncoated tablets into the coating pan and control the following conditions: inlet air temperature 70 ± 10 °C, tablet bed temperature 50 ± 5 °C, outlet air temperature 55 ± 10 °C, and injection pressure 0.4 MPa. Then, the coating liquid was sprayed onto the tablet surface to form a film, thereby obtaining a coated tablet.

Test example 1
According to the process requirements of the above example, raw materials and preparation processes for preparing multiple vitamin and mineral tablets were selected, and changes in the tablets were observed for one day at 37°C and 75% RH. The changes are shown in Figure 1.

According to the process requirements of the comparative example above, raw materials and preparation processes for preparing multiple vitamin and mineral tablets were selected, and changes in the tablets were observed for one day at 37°C and 75% RH. The changes are shown in Figure 2.

According to the process requirements of the above comparative example, raw materials and preparation processes for preparing multiple vitamin and mineral tablets were selected, and changes in the tablets were observed for one day at 37°C and 75% RH, and the weight of the tablets was The increase is shown in Figure 3.

For the above examples, after tableting and coating for 2 months according to the designed amount of nutrients, put into HDPE bottle, add 4g of desiccant, seal and cap, store at 37℃, 75%RH. The stability of the tablet components was investigated in a constant temperature acceleration box. After 3 months, the content of nutrients in the accelerated test samples was detected and the results are shown in the table below.

Experimental Results In each example, tablets were prepared according to the process described in the present invention and provided with a colorless transparent coating. The color of the tablet was pale yellow and uniform. Under high temperature and high humidity conditions, the color of the tablets was relatively stable. In each comparative example, the tablets exhibited problems such as browning and spots during the high temperature and high humidity accelerated process due to the unreasonable compatibility of some materials, immature processes, and high hygroscopicity.

In addition, except for Comparative Examples 1 and 2, all other Examples and Comparative Examples had small weight increase rates, indicating that the tablets of the present invention had low moisture absorption and good tablet stability. Moreover, the results of measuring the nutrient content in the example samples after 3 months of the accelerated stability test showed that the tablets of the present invention had good stability.

Test Example 2: Effect of choline bitartrate treatment process on hygroscopicity of tablets Choline is an important nutrient for the human body, but its common compound form, choline bitartrate, is highly hygroscopic and can absorb water in tablets. It is easy to attract and has a certain influence on the stability of other materials. In this example, the effects of different choline bitartrate treatment processes on the hygroscopicity of tablets were investigated.

1. Preparation of polyethylene glycol-coated choline: Take appropriate amount of polyethylene glycol, dissolve it in water to get coating liquid for later use, add choline bitartrate in the fluidized bed, and spray the coating liquid to make polyethylene glycol-coated choline. I got it. The content of choline bitartrate was 90%.

2. Fatty acid mono- and diglyceride embedding process: Take an appropriate amount of choline bitartrate, put it into the stirring granulator, turn it on, take an appropriate amount of fatty acid mono- and diglyceride, melt it, and under stirring, fatty acid mono- and diglyceride and choline bitartrate. were mixed, granulated, and trimmed. The content of choline bitartrate was 70%.

3. Microcrystalline cellulose blending and granulation process: Microcrystalline cellulose was mixed with choline bitartrate, placed in a fluidized bed, and granulated with hydroxypropyl methylcellulose as a binder. The content of choline bitartrate was 70%.

4. Polyethylene glycol freeze-drying process: Polyethylene glycol was dissolved in water, choline bitartrate was dissolved therein, stirred to completely dissolve, freeze-dried in a freeze dryer, and granulated. The content of choline bitartrate was 90%.

5. Silicon dioxide embedding process: An appropriate amount of silicon dioxide was taken and mixed uniformly with choline bitartrate in a three-dimensional mixer. The content of choline bitartrate was 95%.

6. Ethyl cellulose microencapsulation process (process of the present application): Take an appropriate amount of choline bitartrate, pass through an 80 mesh sieve, take an appropriate amount of corn starch, silicon dioxide, and ethyl cellulose, mix uniformly, and then mix well with a high-speed homogenizer. The solution was dissolved and dried with a spray dryer to obtain a sample with a choline bitartrate content of 95%.

7. Polyvinyl alcohol microencapsulation process: Take an appropriate amount of choline bitartrate, pass through an 80 mesh sieve, take an appropriate amount of corn starch, silicon dioxide, and polyvinyl alcohol, mix well, then mix and dissolve thoroughly with a high-speed homogenizer, and then dry with a spray dryer. A sample with a choline bitartrate content of 95% was obtained.

8. β-Cyclodextrin spray drying process: Take an appropriate amount of choline bitartrate, pass through an 80-mesh sieve, take an appropriate amount of corn starch, silicon dioxide, and β-cyclodextrin, mix and dissolve well with a high-speed homogenizer, and use a spray dryer. A sample was dried and had a choline bitartrate content of 95%.

The prepared sample was added to the mixed raw material of multiple vitamin and mineral tablets according to the actual amount of choline, and the tablet was compressed while controlling the weight and hardness of the tablet.The specific operation was as in Example 1. The same was true. The hygroscopic properties of the tablets were examined at 37° C. and 75% RH.

In the control group, no choline was used.
The experimental results show that the tablets prepared according to the present invention have better moisture-proofing performance and have significant advantages compared to other manufacturing methods.

Although specific models for carrying out the invention have been described in detail, those skilled in the art will be able to make various modifications and substitutions to those details in accordance with all the teachings disclosed. It will be understood that all are within the scope of the present invention. The full scope of the invention is given by the following claims and their equivalents.

Claims (12)

Choline-containing composition of multiple vitamins and minerals, including the following ingredients:
Ingredient 1: Choline bitartrate;
Ingredient 2: The following nutrients: Minerals including calcium, magnesium, iron, zinc, and selenium;
Ingredient 3: Vitamins including the following nutrients: vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, pantothenic acid, vitamin B ₂ , vitamin B ₁₂ , and folic acid;
Ingredient 4: Ascorbyl palmitate. Choline bitartrate is present in the form of a separate pharmaceutical unit, for example in the form of microcapsules;
Preferably, in addition to choline bitartrate, the microcapsule further comprises a filler and a capsule material;
Preferably, the filler is selected from the group consisting of corn starch, microcrystalline cellulose, dextrin and maltodextrin;
Composition according to claim 1, wherein preferably the capsule material is selected from the group consisting of ethylcellulose, cellulose acetate and hydroxypropylcellulose. the mineral is present in the form of a separate pharmaceutical unit, for example in the form of mineral granules;
Preferably, in addition to the nutrients, the mineral granules further include a binding agent;
3. A composition according to claim 1 or 2, wherein preferably the binder is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, povidone, copovidone and gelatin. Ingredient 3 does not contain vitamin C;
Preferably, the components contained in component 3 are divided into the following two groups:
Group 1: vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid;
Group 2: vitamin _B2 , vitamin _B12 , and folic acid,
The first group further comprises a filler; preferably the filler is selected from the group consisting of starch, microcrystalline cellulose, dextrin and maltodextrin;
The second group further comprises a lubricant; preferably the lubricant is selected from the group consisting of silicon dioxide, magnesium stearate, talcum powder and micronized silica gel;
Composition according to any one of claims 1 to 3, wherein preferably the first group and the second group are mixed separately and then combined. In weight percent, the content of each nutrient in the composition is
0.16-0.80 parts vitamin A, 0.002-0.015 parts vitamin D, 5-150 parts vitamin E, 0.015-0.10 parts vitamin K, 0.5-20 parts of vitamin B ₁ , 0.5-20 parts of vitamin B ₂ , 0.5-10 parts of vitamin B ₆ , 0.0005-0.01 parts of vitamin B ₁₂ , 3-15 parts of niacin, 0.08 ~0.50 parts folic acid, 0.01-0.10 parts biotin, 1-20 parts pantothenic acid, 30-500 parts vitamin C, 100-1000 parts choline, 200-1000 parts calcium, 65 ~350 parts magnesium, 5-20 parts iron, 3-15 parts zinc, 10-100 parts selenium,
The raw material that provides vitamin C is ascorbyl palmitate;
The composition according to any one of claims 1 to 4, wherein the raw material supplying choline is choline bitartrate. tablets or capsules;
Preferably, based on a calculation of 2000 tablets/capsules, the composition comprises the following nutrients:
80-400 mg vitamin A, 1-7.5 mg vitamin D, 2.5-75 g vitamin E, 7.5-50 mg vitamin K, 0.25-10 g vitamin B ₁ , 0.25-10 g Vitamin B ₂ , 0.25-5g vitamin B ₆ , 0.25-5mg vitamin B ₁₂ , 1.5-7.5g niacin, 40-250mg folic acid, 5-50mg biotin, 0.5-5g 10g pantothenic acid, 15-250g vitamin C, 50-500g choline, 100-500g calcium, 32.5-175g magnesium, 2.5-10g iron, 1.5-7.5g zinc, 5 ~50g of selenium. A method of preparing a composition according to any one of claims 1 to 6, comprising the steps of:
(1) Prepare choline bitartrate microcapsules;
(2) Preparation of mineral granules: mix raw materials supplying calcium, magnesium, iron, and zinc and granulate to obtain mineral granules;
(3) Preparation of vitamin premix: Vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁ , vitamin B ₆ , niacin, biotin, and pantothenic acid are mixed to obtain vitamin premix 1; vitamin B ₂ , vitamin B ₁₂ , and folic acid to obtain vitamin premix 2; mix vitamin premix 1 and vitamin premix 2 to obtain vitamin premix; preferably raw materials providing selenium in step (2). mixed with ingredients providing calcium, magnesium, iron and zinc or mixed with the ingredients of vitamin premix 1 in step (3);
(4) Formulation: mix choline bitartrate microcapsules, mineral granules, vitamin premix and ascorbyl palmitate to obtain a mixed material, then formulate to obtain the required dosage form;
Optionally, further comprising the step of coating the dosage form obtained in step (4). The preparation method according to claim 7, wherein the choline bitartrate microcapsules are prepared by the following steps:
a) mixing choline bitartrate with filler;
b) mixing the capsule material to obtain a coating solution;
c) mixing the products obtained in steps a) and b) and drying to obtain choline bitartrate microcapsules;
Preferably, drying is carried out in a spray dryer and in a fluidized bed, respectively;
Preferably, after drying, a sieving operation is further included;
Preferably the filler and capsule material are as defined in claim 2. In step (2), a binder is added to the mixed raw material and granulation is performed;
Preparation method according to claim 7 or 8, wherein preferably the binder is as defined in claim 3. During the preparation of the vitamin premix 1, the method further comprises adding a filler to the vitamins;
Preferably, during the preparation of vitamin premix 2, the step further comprises adding a lubricant to the vitamins;
A method according to any one of claims 7 to 9, wherein preferably the filler and lubricant are as defined in claim 4. In step (4), the mixed material further includes one or more selected from the group consisting of fillers, binders, and disintegrants;
Preferably, the filler is selected from the group consisting of starch, microcrystalline cellulose and dextrin (e.g. maltodextrin);
Preferably, the binder is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, povidone, copovidone and gelatin;
Preferably, the method according to any one of claims 7 to 10, wherein the disintegrant is croscarmellose sodium. Use of a composition according to any one of claims 1 to 6 in the manufacture of a nutritional supplement.