COMPOSITION OF MULTIVITAMIN FOR STIMULATING GASTROINTESTINAL SYSTEM MOTILITY AND PREPARATION METHOD THEREFOR

Abstract

The present invention relates to a composition of a multivitamin, vitamins B and C, and a preparation method therefor, and in particular, to a composition of a multivitamin, vitamins B and C for stimulating gastrointestinal system motility and a preparation method therefor. The composition is suitable for preventing and/or treating the statuses or diseases related to a lack of gastrointestinal motility.

Claims

1. A composition comprising B vitamins and C vitamins for preventing and/or treating conditions or diseases associated with insufficient gastrointestinal system motility.

2. The composition according to claim 1, wherein the composition comprising B vitamins and C vitamins comprises B vitamins or analogues or derivatives thereof and vitamin C or analogues or derivatives thereof.

3. The composition according to claim 1, wherein the components of the multivitamin BC composition are selected from vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B12, folic acid, biotin, and vitamin C.

4. The composition according to claim 3, wherein the composition comprises the following components based on weight ratio: 10 parts of vitamin B1, 5 parts of vitamin B2, 10 parts of vitamin B3, 10 parts of vitamin B5, 10 parts of vitamin B6, 0.01 part of biotin, 15 parts of vitamin C, 0.04 part of folic acid, and 0.01 part of vitamin B12.

5. Use of a composition comprising B vitamins and C vitamins for preparation of supplementary foods or drugs for preventing and/or treating the conditions or diseases associated with insufficient gastrointestinal motility.

6. The use according to claim 5, wherein the composition comprising B vitamins and C vitamins comprises B vitamins or analogues or derivatives thereof and vitamin C or analogues or derivatives thereof.

7. A multivitamin BC preparation product, wherein it is a combination of three active components, the active components are separately made into granulations, then compressed into a tablet and packaged. The granulations formulation of each active component combination contains one or more active components and fillers, binders, disintegrants, glidants, lubricants and other auxiliary materials. The different active components correspond to the same or different auxiliary materials.

8. The multivitamin BC preparation product according to claim 7, wherein the preparation product is a multivitamin BC three-layer tablet.

9. A preparation method of a multivitamin BC three-layer tablet product, the method comprising the following steps: The active components and auxiliary materials of the first layer are mixed and then granulated to form the total mixed granulations of the first layer. The active components and auxiliary materials of the second layer are mixed and then granulated to form the total mixed granulations of the second layer. The active components and auxiliary materials are mixed and granulated to form the third layer of total mixed granulations. The total mixed granulations of the first layer, the second layer, and the third layer are compressed into a three-layer tablet.

10. A preparation method of three types of multivitamin BC tablets products, the method includes the following steps: The active components and auxiliary materials of the first type of tablet are mixed and then granulated to form the granulations of the first type of tablet. The active components and auxiliary materials of the second type of tablet are mixed and then granulated to form the granulations of the second type of tablet. The active components and auxiliary materials of the third type of tablet are mixed and then granulated to form the granulations of the third type of tablet. The mixed granulations of the three types of tablets are transferred to a rotary tablet press for pressing to obtain three different types of tablets and coated respectively. The three types of tablets are packaged separately or mixed and then packaged in different bottles, bags or medical containers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0060] FIG. 1: Effects of single dose of 9 components multivitamin BC on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0061] FIG. 2: Effects of single dose of combination 1 or combination 2 (8 components multivitamin BC) on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0062] FIG. 3: Effects of single dose of combination 3 or combination 4 (8 components multivitamin BC) on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0063] FIG. 4: Effects of single dose of combination 5 or combination 6 (8 components multivitamin BC) on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0064] FIG. 5: Effects of single dose of combination 7, combination 8 or combination 9 (8 components multivitamin BC) on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0065] FIG. 6: Effects of single dose of multivitamin BC on the ATP content of energy metabolism of small intestinal in mice.

[0066] FIG. 7. Effects of multiple doses of multivitamin BC on small intestine propulsion function in mice with loperamide-induced constipation.

[0067] FIG. 8. Effects of multiple doses of 9 components multivitamin BC on the ATP content of energy metabolism of small intestinal in mice.

DETAILED DESCRIPTION

Example 1: Effects of Single Dose of 9 Components Multivitamin BC on the Small Intestinal Propulsive Rate in Mice with Loperamide-Induced Constipation

1.1 Experimental Methods

[0068] The 20-25 g male mice of C57BL/6 were selected. The experimental animals were randomly divided into normal control group, loperamide model group, 9 components multivitamin BC low dose group (0.75×), multivitamin BC moderate dose group (1.5×) and multivitamin BC high dose group (3×). After fasting and freely drinking for about 22-24 hours, each group of the mice were intragastrically administrated at above doses at 20 ml/kg. After 30 minutes of administration, the control group was injected subcutaneously with the saline solution containing 1.0% Tween 80 while the other groups were injected subcutaneously with loperamide in an injection volume of 10 ml/kg. After a subcutaneous injection for 30 minutes, an intragastric administration of the charcoal solution was performed at an administration volume of 10 ml/kg. Twenty minutes after an intragastric administration of the charcoal solution, the animal was sacrificed by cervical dislocation and its abdominal cavity was immediately opened to separate the mesentery. The intestinal canal from the pylorus to the ileocecal junction was carefully removed and put on a tray. Be careful not to involve the small intestine, gently place the small intestine in a straight line, and measure the total length of the small intestine. The length from the pylorus to the front of the charcoal solution is the propulsive distance of the charcoal solution, and the small intestinal propulsive rate (%) of the charcoal solution was calculated. Small intestinal propulsive rate (%)=(the propulsive distance of the charcoal solution/the total length of the small intestine)×100%.

1.2 Experimental Drug

[0069] Composition list of multivitamin BC (mice):

TABLE-US-00001 9 components of multivitamin BC No. Components Dose (1X mg/kg) 1 VB1 19.68 2 VB2 10.25 3 VB3 19.885 4 VB5 21.32 5 VB6 20.5 6 VC 30.75 7 VB7 0.0205 8 VB9 0.082 9 VB12 0.0205

1.3 Experimental Results

[0070] The experimental results (FIG. 1) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the control group. The small intestinal propulsive rate of mice was significantly increased after administration of the moderate dose of 9 components multivitamin BC. With the increase of the dose, the small intestinal propulsive effect of high dose 9 components multivitamin BC increased more obviously in a dose-dependent manner (N=16).

Example 2: Screening the Effect of 8 Components of Multivitamin BC Administration on the Small Intestinal Propulsive Rate in Mice with Loperamide-Induced Constipation

2.1 Experimental Methods

[0071] The 8 component group is a combination of components removing any one component from the 9 components. They are 8-component combination 1 (removed B1), 8-component combination 2 (removed B2), 8-component combination 3 (removed B3), 8-component combination 4 (removed B5), 8-component combination 5 (removed B6)), 8-component combination 6 (removed VC), 8-component combination 7 (removed B7), 8-component combination 8 (removed B9), 8-component combination 12 (removed B12). 2.2 Experimental drug

TABLE-US-00002 8-component combination table 8-component combination of multivitamin BC No. Component was removed Dose (1X mg/kg) 1 VB1 19.68 2 VB2 10.25 3 VB3 19.885 4 VB5 21.32 5 VB6 20.5 6 VC 30.75 7 VB7 0.0205 8 VB9 0.082 9 VB12 0.0205

2.3 Experimental Results

[0072] 2.3.1 Effects of Single Dose of Combination 1 or Combination 2 (8 Components Multivitamin BC) on the Small Intestinal Propulsive Rate in Mice with Loperamide-Induced Constipation.

[0073] The experimental results (FIG. 2) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the normal control group. The small intestinal propulsive rate of mice was significantly higher than the model group after administration of the 9 components multivitamin BC. The small intestinal propulsive rate were improved to a certain extent after the administration of 8 components combination 1 or combination 2 (N=8-10). 2.3.2 Effects of single dose of combination 3 or combination 4 (8 components multivitamin BC) on the small intestinal propulsive rate in mice with loperamide-induced constipation.

[0074] The experimental results (FIG. 3) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the normal control group. The small intestinal propulsive rate of mice was significantly higher than the model group after administration of the 9 components multivitamin BC. The small intestinal propulsive rate increased significantly after the administration of 8 components combination 3. The small intestinal propulsive rate were improved to a certain extent after the administration of 8 components combination 4 (removed vitamin B5) (N=8-10).

2.3.3 Effects of Single Dose of Combination 5 or Combination 6 (8 Components Multivitamin BC) on the Small Intestinal Propulsive Rate in Mice with Loperamide-Induced Constipation.

[0075] The experimental results (FIG. 4) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the normal control group. The small intestinal propulsive rate of mice was significantly higher than the model group after administration of the 9 components multivitamin BC. The small intestinal propulsive rate were improved to a certain extent after the administration of 8 components combination 5 or combination 6 (N=8-10).

2.3.4 Effects of Single Dose of Combination 7 or Combination 8 or Combination 9 (8 Components Multivitamin BC) on the Small Intestinal Propulsive Rate in Mice with Loperamide-Induced Constipation.

[0076] The experimental results (FIG. 5) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the normal control group. The small intestinal propulsive rate of mice was significantly higher than the model group after administration of the 9 components multivitamin BC. The small intestinal propulsive rate were improved to a certain extent after the administration of 8 components combination 7 or combination 8 or combination 9 (N=8-10).

Example 3: Effects of Single Dose of Multivitamin BC on the ATP Content of Energy Metabolism of Small Intestinal in Mice

3.1 Experimental Methods

[0077] The 20-25 g male mice of C57BL/6 were selected. The experimental animals were randomly divided into normal control group, 9 components multivitamin BC low dose group (0.75×), multivitamin BC moderate dose group (1.5×) and multivitamin BC high dose group (3×). After fasting and freely drinking for about 22-24 hours, each group of the mice were intragastrically administrated at above doses at 20 ml/kg. After 30 minutes of administration, the animal was sacrificed by cervical dislocation. The upper intestinal tube about 3 cm from the pylorus was cutted, putted into normal saline for cleaning, and the chyme was removed. Then dry it with absorbent paper and put it into 1.5 ml EP tube for liquid nitrogen quick-freezing. After it was ground into powder in liquid nitrogen, ATP was extracted. The Phenol-TE (50 mg to 1 mL) was added, thoroughly mixed, and left for 10 min at room temperature. The supernatant was obtained after centrifuged at 12000 g for 10 min. 1 mL of sample was mixed with 200 uL chloroform and 600 uL deionized water, Oscillating 20 s mixed, centrifuged at 12000 g for 10 min to obtain the supernatant, and 20 uL sample was added to 100 uL ATP test solution (Kit of Biyuntian) to determine the luminescence value.

3.2 Experimental Results

[0078] The experimental results (FIG. 6) showed that the small intestinal ATP content of mice was increased after administration of 9 components of multivitamin BC, and compared with the normal group, the small intestinal ATP content of the high-dose group was significantly increased (N=35-39).

Example 4: Effects of Multiple Doses of Multivitamin BC on Small Intestine Propulsion Function in Mice with Loperamide-Induced

Constipation. 4.1 Experimental Methods

[0079] The 20-25 g male mice of C57BL/6 were selected. The experimental animals were randomly divided into normal control group, loperamide model group, 9 components multivitamin BC low dose group (0.75×), multivitamin BC moderate dose group (1.5×) and multivitamin BC high dose group (3×). The administration was continued for seven days, and the daily dose was divided into two doses, once in the morning and once in the afternoon. After fasting and freely drinking for about 22-24 hours from the 8th day, each group of the mice were intragastrically administrated at above doses at 20 ml/kg. After 30 minutes of administration, the animals were injected subcutaneously with 2.5 mg/kg loperamide (in saline solution containing 1.0% Tween 80) in an injection volume of 10 ml/kg. After a subcutaneous injection for 30 minutes, an intragastric administration of the charcoal solution was performed at an administration volume of 10 ml/kg. Twenty minutes after an intragastric administration of the charcoal solution, the animal was sacrificed by cervical dislocation and its abdominal cavity was immediately opened to separate the mesentery. The intestinal canal from the pylorus to the ileocecal junction was carefully removed and put on a tray. Be careful not to involve the small intestine, gently place the small intestine in a straight line, and measure the total length of the small intestine. The length from the pylorus to the front of the charcoal solution is the propulsive distance of the charcoal solution, and the small intestinal propulsive rate (%) of the charcoal solution was calculated. Small intestinal propulsive rate (%)=(the propulsive distance of the charcoal solution/the total length of the small intestine)×100%.

4.2 Experimental Results

[0080] The experimental results (FIG. 7) showed that the small intestinal propulsive rate in the model group was significantly lower than that in the normal control group. The small intestinal propulsive rate of mice was significantly increased after administration of multiple doses of 9 components multivitamin BC. The small intestinal propulsive effect of low dose 9 components multivitamin BC was equivalent to the high dose (N=30).

Example 5: Effects of Multiple Doses of 9 Components Multivitamin BC on the ATP Content of Energy Metabolism of Small Intestinal in Mice

5.1 Experimental Methods

[0081] The 20-25 g male mice of C57BL/6 were selected. The experimental animals were randomly divided into normal control group, loperamide model group, 9 components multivitamin BC low dose group (0.75×), multivitamin BC moderate dose group (1.5×) and multivitamin BC high dose group (3×). The administration was continued for seven days, and the daily dose was divided into two doses, once in the morning and once in the afternoon. After fasting and freely drinking for about 22-24 hours from the 8th day, each group of the mice were intragastrically administrated at above doses at 20 ml/kg. The animal was sacrificed by cervical dislocation thirty minutes later. The upper intestinal tube about 3 cm from the pylorus was cutted, putted into normal saline for cleaning, and the chyme was removed. Then dry it with absorbent paper and put it into 1.5 ml EP tube for liquid nitrogen quick-freezing. After it was ground into powder in liquid nitrogen, ATP was extracted. The Phenol-TE (50 mg to 1 mL) was added, thoroughly mixed, and left for 10 min at room temperature. The supernatant was obtained after centrifuged at 12000 g for 10 min. 1 mL of sample was mixed with 200 uL chloroform and 600 uL deionized water, Oscillating 20 s mixed, centrifuged at 12000 g for 10 min to obtain the supernatant, and 20 uL sample was added to 100 uL ATP test solution (Kit of Biyuntian) to determine the luminescence value.

5.2 Experimental Results

[0082] The experimental results (FIG. 8) showed that the small intestinal ATP content of mice was increased after administration of multiple doses of 9 components multivitamin BC, and compared with the normal group, the small intestinal ATP content of the high-dose group was significantly increased (N=36-40). It showed that multivitamin BC may treat constipation by improving the energy metabolism in the small intestine.

Example 6: Preparation Process of Multivitamin BC Three-Layer Tablet

6.1 Preparation of the Total Mixed Granulations of the First Layer

6.1.1 VB1 VB2/VB3/VB6 Granulations

[0083]

TABLE-US-00003 TABLE 1 the formula of VB1/VB2/VB3/VB6 granulations component mg/tablet VB1 48 VB2 25 VB3 48 VB6 50

[0084] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

6.1.2 Folic Acid Granulations

[0085]

TABLE-US-00004 TABLE 2 the formula of folic acid granulations component mg/tablet Folic acid 0.2

[0086] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

6.1.3 VB12 Granulations

[0087]

TABLE-US-00005 TABLE 3 the formula of VB12 granulations component mg/tablet VB12 0.05

[0088] Microcrystalline, silicon dioxide, gelatin, and other excipients were added to prepare binders and load drug.

6.1.4 Mixing Process

[0089]

TABLE-US-00006 TABLE 4 the formula of the total mixed granulations of the first layer component mg/tablet VB1/VB2/VB3/VB6 392.5 granulations folic acid granulations 48.0 VB12 granulations 53.71

[0090] Microcrystalline, silicon dioxide, magnesium stearate, and other excipients were mixed to obtain the first layer of total mixed granulations.

6.2 Preparation of the Total Mixed Granulations of the Second Layer

6.2.1 VC Granulations

[0091]

TABLE-US-00007 TABLE 5 the formula of VC granulations component mg/tablet VC 75

[0092] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

6.2.2 Calcium Pantothenate Granulations

[0093]

TABLE-US-00008 TABLE 6 the formula of calcium pantothenate granulations component mg/tablet calcium pantothenate 52

[0094] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

6.2.3 Mixing Process

[0095]

TABLE-US-00009 TABLE 7 the formula of the total mixed granulations of the second layer component mg/tablet VC granulations 183.6 calcium pantothenate 196.13 granulations

[0096] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were mixed to obtain the second layer of total mixed granulations.

6.3 the Total Mixed Granulations of the Third Layer

6.3.1 Biotin Granulations

[0097]

TABLE-US-00010 TABLE 8 the formula of biotin granulations component mg/tablet biotin 0.05

[0098] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were premixed. The granulations were transferred to a fluidized bed for coating, and 15% (w/w) coating fluid was added, the weight of the granulations increased 20% theoretically.

6.3.2 the Blank Granulations

[0099] The blank granulations were prepared as follows: Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

6.3.3 Mixing Process

[0100]

TABLE-US-00011 TABLE 9 the formula of the total mixed granulations of the third layer component mg/tablet biotin granulations 63.78 blank granulations 172.75

[0101] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were mixed to obtain the third layer of total mixed granulations.

6.4 the Preparation of the Three Layers Tablet

[0102] The total mixed granulations of the first layer were poured into the first material funnel of the three-layer tablet machine, operating the tablet press, and adjusting the parameters so that the tablet weight reached ±5% of the target tablet weight. Then the total mixed granulations of the second layer were poured into the second material funnel, adjusting the parameters so that the total weight (the first layer piece+the second layer piece) reached ±5% of the target tablet weight. Finally the total mixed granulations of the third layer were poured into the third material funnel, adjusting the parameters so that the total weight (the first layer piece+the second layer piece+the third layer piece) reached ±5% of the target piece weight. After the weight and hardness of the three-layer tablet were stabilized, the tablet was formally compressed.

6.5 Coating

[0103] The core was putted into the coating pan. The coating weight was increased by 3%˜4%.

6.6 Packaging

Example 7: Preparation of Multivitamin BC Capsule

7.1 the First Type of Tablet (VB Tablet)

7.1.1 the Granulations of VB1/VB2/VB3/VB6

[0104]

TABLE-US-00012 TABLE 10 The formula of VB1/VB2/VB3/VB6 granulations component mg/tablet VB1 8 VB2 4.17 VB3 8 VB6 8.33

[0105] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

7.1.2 Folic Acid Granulations

[0106]

TABLE-US-00013 TABLE 11 the formula of folic acid granulations component mg/tablet Folic acid 0.33

[0107] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

7.1.3 VB12 Granulations

[0108]

TABLE-US-00014 TABLE 12 the formula of VB12 granulations component mg/tablet VB12 0.0083

[0109] Microcrystalline, silicon dioxide, gelatin, and other excipients were added to prepared binders and load drug.

7.1.4 Mixing Process and Tabletting

[0110]

TABLE-US-00015 TABLE 13 the formula of the total mixed granulations of the VB tablet component mg/tablet VB1/VB2/VB3/VB6 65.42 granulations folic acid granulations 8.00 VB12 granulations 8.95

[0111] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were added. The total mixed granulations of VB tablets were obtained by weight according to the prescription. The total mixed granulations were poured into a tablet machine, and formally started tabletting after the tablet weight and hardness were stable to obtain VB tablets.

7.2 the Second Type of Tablet (VC/P Tablet)

7.2.1 VC Granulations

[0112]

TABLE-US-00016 TABLE 14 the formula of VC granulations component mg/tablet VC 18.75

[0113] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

7.2.2 Calcium Pantothenate Granulations

[0114]

TABLE-US-00017 TABLE 15 the formula of VC granulations component mg/tablet calcium pantothenate 13

[0115] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

7.2.3 Mixing Process and Tabletting

[0116]

TABLE-US-00018 TABLE 16 the formula of the total mixed granulations of the VC/P tablet component mg/tablet VC granulations 45.9 calcium pantothenate 49.03 granulations

[0117] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were added, mixed to form the total mixed granulations of the VC/P tablet. The total mixed granulations were poured into a tablet machine, and formally started tabletting after the tablet weight and hardness were stable to obtain VC/P tablets.

7.3 the Third Type of Tablet (Biotin Tablet)

7.3.1 Biotin Granulations

[0118]

TABLE-US-00019 TABLE 17 the formula of biotin granulations component mg/tablet biotin 0.025

[0119] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, other excipients, and film coating were premixed. The granulations were transferred to a fluidized bed for coating, and 15% (w/w) coating fluid was added, The weight of the granulations increased 20% theoretically.

7.3.2 Mixing Process and Tabletting

[0120]

TABLE-US-00020 TABLE 18 the formula of the total mixed granulations of the biotin component mg/tablet biotin granulations 76.80

[0121] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were added, mixed to form the total mixed granulations of the biotin. The total mixed granulations were poured into a tablet machine, and formally started tabletting after the tablet weight and hardness were stable to obtain biotin tablets.

7.4 Coating

[0122] The core was putted into the coating pan and the coating weight was increased by 3%-4%.

7.5 Filling Capsules

[0123] By using a capsule filling machine, 3 VB tablets, 2 VC/P tablets and one biotin tablet were filled into the one capsule.

7.6 Packaging

[0124] High density polyethylene bottle or blister were used for packaging.

Example 8: Preparation of Multivitamin BC Three Types of Tablets

8.1 the First Type of Tablet

8.1.1 VB1 VB2/VB3/VB6 Granulations

[0125]

TABLE-US-00021 TABLE 19 the formula of VB1/VB2/VB3/VB6 granulations component mg/tablet VB1 48 VB2 25 VB3 48 VB6 50

[0126] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

8.1.2 Folic Acid Granulations

[0127]

TABLE-US-00022 TABLE 20 the formula of folic acid granulations component mg/tablet Folic acid 0.2

[0128] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

8.1.3 VB12 Granulations

[0129]

TABLE-US-00023 TABLE 21 the formula of VB12 granulations component mg/tablet VB12 0.05

[0130] Microcrystalline, silicon dioxide, gelatin, and other excipients were added to prepare binders and load drug.

8.1.4 Mixing Process

[0131]

TABLE-US-00024 TABLE 22 the formula of the total mixed granulations of the first type of tablet component mg/tablet VB1/VB2/VB3/VB6 392.5 granulations folic acid granulations 48.0 VB12 granulations 53.71

[0132] Microcrystalline, silicon dioxide, magnesium stearate, and other excipients were mixed to obtain the first type of tablet of total mixed granulations.

8.1.5 Mixed the Total Mixed Granules and Tabletting

8.1.6 Coating

[0133] The tablets were coated with a transparent film, and the weight after coating increased by 1.5%-4%.

8.2 the Second Type of Tablet

8.2.1 VC Granulations

[0134]

TABLE-US-00025 TABLE 23 the formula of VC granulations component mg/tablet VC 75

[0135] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

8.2.2 Calcium Pantothenate Granulations

[0136]

TABLE-US-00026 TABLE 24 the formula of calcium pantothenate granulations component mg/tablet calcium pantothenate 52

[0137] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

8.2.3 Mixing Process

[0138]

TABLE-US-00027 TABLE 25 the formula of the total mixed granulations of the second type of tablet component mg/tablet VC granulations 183.6 calcium pantothenate 196.125 granulations

[0139] Sodium carboxymethyl starch, silicon dioxide, magnesium stearate, and other excipients were mixed to obtain the second type of tablet of total mixed granulations.

8.2.4 Mixed the Total Mixed Granules and Tabletting

8.2.5 Coating

[0140] The tablets were coated with a transparent film, and the weight after coating increased by 1.5%-4%.

8.3 the Third Type of Tablet

8.3.1 Biotin Granulations

[0141]

TABLE-US-00028 TABLE 26 the formula of biotin granulations component mg/tablet biotin 0.05

[0142] Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, other excipients, and film coating were premixed. The granulations were transferred to a fluidized bed for coating, and 15% (w/w) coating fluid was added. The weight of the granulations was increased 20% theoretically.

8.3.2 the Blank Granulations

[0143] The blank granulations were prepared as follows: Microcrystalline cellulose, mannitol, sodium carboxymethyl starch, povidone K30, and other excipients were added to pretreat raw materials and prepare binders. The materials were mixed in dry conditions for 10 minutes. Soft materials were obtained by wet granulation. Then the product was obtained by wet screening, drying and granulation.

8.3.3 Mixing Process

[0144]

TABLE-US-00029 TABLE 27 the formula of the total mixed granulations of the third type of tablet component mg/tablet biotin granulations 63.78 blank granulations 172.75

[0145] Sodium carboxymethyl starch, silicon dioxide, and magnesium stearate were mixed to obtain the third type of tablet of total mixed granulations.

8.3.4 Mixed the Total Mixed Granules and Compressed Tablets

8.3.5 Coating

[0146] The tablets were coated with a transparent film, and the weight after coating increased by 1.5%-4%.

8.4 Package

[0147] Putted the three types of tablets into bottles respectively.

Example 9: Study on the Stability of Multivitamin BC

9.1 Stability Study of Monolayer Tablet

[0148] VC granulations and VB1/VB2/VB3/VB6/calcium pantothenate/choline ditartrate/folic acid/biotin/VB12 granulations were mixed according to the proportion of the three multivitamin BC tablets, and were compressed into monolayer tablets, and the stability was preliminarily tested. The detection methods for each component are listed below:

9.1.1 Test Methods for VB12 and Biotin

[0149]

TABLE-US-00030 TABLE 28 HPLC system for the detection of VB12 and biotin System The HPLC system includes a pump, an automatic sampler, and a column thermostat chromatographic Agilent ZORBAX SB-C18, 4.6 × 150 mm, 5-micron column Detector DAD detector, detection wavelength, 210 nm, 360 nm

9.1.2 Test Methods for Folic Acid

[0150]

TABLE-US-00031 TABLE 29 HPLC system for the detection of folic acid System The HPLC system includes a pump, an automatic sampler, and a column thermostat chromatographic Waters Atlantis ®T3, 4.6 × 250 mm, 5-micron column Detector DAD detector, detection wavelength, 300 nm

9.1.3 Test Methods for Calcium Pantothenate

[0151]

TABLE-US-00032 TABLE 30 HPLC system and chromatographic parameters for the detection of calcium pantothenate System The HPLC system includes a pump, an automatic sampler, and a column thermostat chromatographic Waters Atlantis ®T3, 4.6 × 250 mm, 5-micron column ultraviolet DAD detector, detection wavelength, 210 nm detector

9.1.4 Test Methods for VB1, VB2, VB3, and VB6

[0152]

TABLE-US-00033 TABLE 31 HPLC system and chromatographic parameters for the detection of folic acid System The HPLC system includes a pump, an automatic sampler, and a column thermostat chromatographic Waters Atlantis ®T3, 4.6 × 250 mm, 5-micron column Detector DAD detector, detection wavelength, 280 nm

9.1.5 Test Methods for VC

[0153] Twenty tablets were grinded thoroughly. The powder equivalent to about 0.2 g of vitamin C of the test substance was weight accurately, putted into an iodine bottle, accurately measured freshly boiled water and diluted acetic acid into the iodine bottle, oscillation the bottle after ultrasonic vibration for 5 minutes, filtered quickly, accurately measured 50 mL of the filtrate and putted it into another iodine bottle, added titration indicator into the bottle, and titrated with iodine titrant immediately after oscillating until the solution turning blue and did not fade within 30 s.

[0154] Results: The content of folic acid, biotin, VB12 and VB1 decreased in the intermediate and long-term conditions for 2 months, and the remaining components were basically stable. It indicated that the interaction between the components in the monolayer tablet may be exist except for the possibility of self-degradation, and the formulation preparation process needs to be developed again.

TABLE-US-00034 TABLE 32 The content of each component in the stability test of multivitamin BC monolayer tablets Content long-term −20° C./ 4° C./ conditions/ intermediate/ Name component 0 Day 2 months 2 months 2 months 2 months VBC folic acid 97%  95%  92% 86% 76% monolayer biotin 101%  102%  98% 89% 79% tablets VB12 97% 102% 101% 99% 90% niacin 99% 103%  97% 97% 102%  VB6 97% 101% 101% 103%  102%  VB1 97% 102% 101% 93% 84% VB2 98% 101% 102% 102%  101%  VC 97% 100% 100% 97% 96% calcium 114%  102% 102% 98% 93% pantothenate choline 108%   93%  94% 96% 96% bitartrate

9.2 Stability Study of Three-Layer Tablets

[0155] The three-layer multivitamin BC tablets were produced according to the preparation process in Example 6, the test method of each component was the same as that of the monolayer tablet, and the content results of the stability test (3.5 months) were showed below:

TABLE-US-00035 TABLE 33 The content of each component in the stability test of multivitamin BC three-layer tablets content long-term 4° C./ conditions/ intermediate/ accelerated/ Name component 0 day 2 month 2 months 2 months 2 months VBC VC 99.94% 99.70% 99.15% 98.36% 100.87% three- VB1 99.63% 99.22% 98.73% 96.90% 98.49% layer VB2 99.50% 102.49% 101.99% 99.47% 101.27% tablets VB3 99.47% 101.63% 101.17% 99.02% 100.55% VB6 99.90% 102.70% 103.36% 101.47% 101.37% folic acid 99.63% 99.66% 98.47% 100.87% 99.80% calcium 101.46% 101.68% 101.44% 101.42% 101.12% pantothenate biotin 98.21% 98.43% 84.73% 78.61% 69.04% VB12 101.93% 103.68% 102.37% 102.74% 99.45%

9.3 Study on the Stability of Multivitamin Capsules

[0156] The multivitamin BC capsules were produced according to the preparation process in Example 7, the test method of each component was the same as that of the monolayer tablet, and the content results of the stability test were showed below:

TABLE-US-00036 TABLE 34 The content of each component in the stability test of multivitamin BC capsules content intermediate/ accelerated/ long-term/ intermediate/ Name component 0 month 2 months 2 months 3 months 3 months VBC biotin 99.19% 97.46% 93.86% 97.72% 95.61% capsules VC 97.06% 96.25% 97.00% 97.46% 97.04% calcium 102.10% 102.36% 102.06% 101.17% 102.05% pantothenate VB12 102.67% 100.33% 95.41% 99.68% 99.38% folic acid 101.81% 102.59% 101.41% 102.94% 101.12% VB1 93.78% 94.07% 90.84% 93.02% 97.83% VB2 94.57% 94.28% 93.05% 93.42% 97.23% VB3 92.10% 93.33% 91.67% 92.39% 93.42% VB6 93.66% 93.18% 91.24% 91.64% 88.39%

9.4 Stability Study of Three Types of Tablets

[0157] The multivitamin BC three types of tablets were produced according to the preparation process in Example 8, the detection method of each component was the same as that of the monolayer tablet, and the content results of the stability test were showed below:

TABLE-US-00037 TABLE 35 The content of each component in the stability test of multivitamin BC three types of tablet Content accel- accel- accel- erated/1 erated/2 erated/3 Name Component 0 day months months months VBC VB12 101.69% 100.12% 96.99% 98.32% three folic acid 101.66% 99.02% 98.61% 97.63% types VB1 102.21% 96.72% 94.58% 95.43% of VB2 103.08% 103.49% 102.54% 103.95% tablets niacinamide 102.56% 101.37% 97.51% 97.13% VB6 101.45% 97.19% 95.60% 97.17% VC 94.54% 94.75% 94.14% 94.58% calcium 99.06% 100.82% 98.60% 100.19% pantothenate biotin 98.84% 100.33% 96.60% 97.10%

CONCLUSIONS

[0158] The results of the small intestine propulsion experiment in the treatment of constipated mice by a single dose of 9 components of multivitamin BC showed that 9 components multivitamin BC could effectively restore the small intestinal propulsion rate of constipated mice in the dose-dependent manner and could improve the propulsion function of the small intestine of constipated mice to treat constipation.

[0159] The results of the small intestine propulsion experiment in the treatment of constipated mice by a single dose of 8 components of multivitamin BC showed that the small intestinal propulsive rate were improved to a certain extent after the administration of any 8 components of multivitamin BC (The components of VB1, VB2, VB3, VB5, VB6, VB7, VB9, VC, VB12 was removed separately).

[0160] Compared with multivitamin BC monolayer tablet product, the three-layer tablet multivitamin BC product, the multivitamin BC capsule product and the three types of tablets of multivitamin BC product have a more stable content of each component. The content of VB1, folic acid, VB12 and biotin in the monolayer tablets decreased significantly, while were no obvious decreased in the three-layer tablet product, the capsule product and the three types of multivitamin BC tablets product. It showed that the preparation process of three-layer tablets, capsules and three types of multivitamin BC tablets product could avoid the mutual influence caused by the contact of each component, and effectively ensure the stability of each component.

[0161] In order to describe and understand the present invention more clearly, we describe the present invention by examples in detail. It is clear that modification and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.