CN108926544B - Tetrafolic acid tablet and preparation method thereof - Google Patents
Tetrafolic acid tablet and preparation method thereof Download PDFInfo
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Abstract
The invention provides a tetrahydrofolic acid tablet and a preparation method thereof, which comprises (6S) -5-methyltetrahydrofolic acid, 0.1-15.0 percent of glucosamine salt, 40.0-94.0 percent of diluent, 3.0-42.0 percent of disintegrant and 0.2-12.0 percent of lubricant. The tablet is prepared by adopting a direct powder tabletting process through the steps of mixing, tabletting and the like. The four-generation folic acid tablet prepared by the invention is quickly dissolved in dissolution media in different environments, is beneficial to release in different groups of digestive tract environments, and is quickly absorbed in vivo.
Description
Technical Field
The invention relates to medicine and functional food, in particular to a tetrabasic folic acid tablet and a preparation method thereof.
Background
Folic acid is a water-soluble vitamin essential to the human body and is essential for maintaining cellular function and health. In 1939, Ind Monsanto, a physician, who thought this group of vitamins to be a group of vitamins, called "leaf essence", found that yeast extracts could be used to treat anemia in pregnant women and were very effective; in 1941 a doctor in the united states found a lot of "leaf essence" in spinach and found that this substance is widely present in green leaf vegetables and is therefore called folic acid. Scientists developed 5-methyltetrahydrofolate calcium salt in 1989, which is a representative of the third generation of folic acid, and the third generation is a folic acid derivative, which can directly enter human cells and can be converted into effective folic acid through a series of complex metabolism, unlike the first generation folic acid or the second generation folic acid synthesized. Finally, the fourth generation of folic acid- (6S) -5-methyl tetrahydrofolic acid glucosamine salt is found (No. 8 notice of Wei of the national institutes of health, Commission 2017, molecular formula: C32H51N9O16). The folic acid preparation is widely used in products of pregnant and lying-in women, infants, old people and the like, most of the folic acid preparations in the second generation or the third generation are currently circulated in the market, and the folic acid tablets in the fourth generation and the preparation method thereof are provided for providing more excellent folic acid preparation products.
Disclosure of Invention
The invention aims to provide a fourth-generation folic acid tablet, and aims to provide a processing and preparation method of the fourth-generation folic acid tablet.
In order to achieve the purpose, the invention provides a four-generation folic acid tablet, which consists of (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent, a disintegrating agent and a lubricant, the four-generation folic acid tablet is subjected to a dissolution test by taking 200ml of phosphate buffer solution with pH of 6.8 as a dissolution medium according to a third method of 0931 dissolution and release determination method of the general rule of the four ministry of the national pharmacopoeia 2015 edition, wherein the temperature is 37 ℃, the rotating speed is 50 r/min, and the external dissolution rate is not lower than 85% within 15 minutes;
according to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, 200ml of phosphate buffer solution with the pH value of 7.2 is used as a dissolution medium to perform dissolution test, the temperature is 37 ℃, the rotating speed is 75 r/min, and the dissolution rate in vitro is not lower than 80% in 30 minutes;
according to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, 200ml of purified water is taken as a dissolution medium to carry out dissolution test, the temperature is 37 ℃, the rotating speed is 50 r/min, the 15-minute in vitro dissolution is not lower than 85%, and the 30-minute in vitro dissolution is not lower than 95%;
according to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, 200ml of phosphate buffer solution with the pH value of 5.5 is taken as a dissolution medium to perform dissolution test, the temperature is 37 ℃, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 70% in 30 minutes;
according to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of hydrochloric acid solution with pH of 1.2 as a dissolution medium, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 60% in 30 min;
the four-generation folic acid tablet comprises the following components in percentage by weight:
the diluent of the fourth-generation folic acid tablet is one or a mixture of more than two of pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, erythritol, xylitol, D-mannitol, methylcellulose, copovidone, calcium hydrophosphate, maltitol, hydroxypropyl starch, maltitol, dextrin, ethyl cellulose, soluble starch, anhydrous calcium hydrophosphate, sucrose, starch and milk powder.
The disintegrant of the tetrahydrofolic acid tablet is one or a mixture of more than two of hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
The lubricant of the tetra-folic acid tablet is selected from talcum powder, silicon dioxide, polyethylene glycol, stearic acid, palm wax, magnesium stearate, glyceryl behenate and sodium stearyl fumarate.
According to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, 200ml of phosphate buffer solution with the pH value of 6.8 is used as a dissolution medium to perform dissolution test, the temperature is 37 ℃, the rotating speed is 50 r/min, and the dissolution rate in vitro is not lower than 85% in 15 min; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH7.2 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 75 r/min, and the dissolution rate in vitro is not lower than 81% in 30 minutes; according to a third method of 0931 dissolution and release determination in the four general rules of the national pharmacopoeia 2015 edition, the dissolution test is carried out by taking 200ml of purified water as a dissolution medium, the temperature is 37 ℃, the rotating speed is 50 r/min, the 15-minute in-vitro dissolution rate is not lower than 86%, and the 30-minute in-vitro dissolution rate is not lower than 95%; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH5.5 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 70% in 30 minutes; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 edition of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of hydrochloric acid solution with pH1.2 as a dissolution medium, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 60% in 30 min; the four-generation folic acid tablet comprises: (6S) -5-methyltetrahydrofolic acid, 0.4g of glucosamine salt, 20.0g of pregelatinized starch, 60.0g of microcrystalline cellulose, 6.0g of calcium hydrophosphate, 4.0g of sodium carboxymethyl starch, 4.0g of crospovidone, 4.0g of low-substituted hydroxypropyl cellulose, 1.0g of silicon dioxide and 0.6g of polyethylene glycol.
According to the third method of 0931 dissolution and release determination method which is the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, 200ml of phosphate buffer solution with the pH value of 6.8 is used as a dissolution medium to perform dissolution test, the temperature is 37 ℃, the rotating speed is 50 r/min, and the dissolution rate in vitro is not lower than 85% in 15 min; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH7.2 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 75 r/min, and the dissolution rate in vitro is not lower than 81% in 30 minutes; according to a third method of 0931 dissolution and release determination in the four general rules of the national pharmacopoeia 2015 edition, the dissolution test is carried out by taking 200ml of purified water as a dissolution medium, the temperature is 37 ℃, the rotating speed is 50 r/min, the 15-minute in-vitro dissolution rate is not lower than 86%, and the 30-minute in-vitro dissolution rate is not lower than 95%; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH5.5 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 71% in 30 minutes; according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 edition of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of hydrochloric acid solution with pH1.2 as a dissolution medium, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 62% in 30 min; the four-generation folic acid tablet comprises: (6S) -5-methyltetrahydrofolic acid, 0.9g of glucosamine salt, 80.0g of microcrystalline cellulose, 7.0g of sodium carboxymethyl starch, 11.0g of crospovidone and 1.1g of silicon dioxide.
A preparation method of four-generation folic acid tablets comprises the following steps:
(1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 5-90 minutes, adding a lubricant, and mixing for 3-60 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 80-200N, and coating or not coating to obtain the fourth-generation folic acid tablet.
The invention has the following beneficial effects: the tetrahydrofolic acid tablets are quickly dissolved in dissolution media in different environments, are beneficial to release in digestive tract environments of different groups, are quickly absorbed in vivo, and can relieve and promote tear secretion and relieve xerophthalmia.
Detailed Description
The present invention will be further described with reference to specific embodiments, and the raw materials, reagent materials and the like used in the following examples and test examples are commercially available products unless otherwise specified. The following examples are intended only to illustrate the invention, wherein the experimental procedures, without specific definition, are conventional.
The preparation method of the reagent comprises the following steps:
hydrochloric acid solution at ph 1.2: taking 7.65mL of hydrochloric acid, adding water to dilute the hydrochloric acid to 1000mL, and shaking up to obtain the compound preparation;
0.2mol/L potassium dihydrogen phosphate solution: 27.22g of monopotassium phosphate is taken, dissolved by water and diluted to 1000 mL;
0.2mol/L sodium hydroxide solution: 8.00g of sodium hydroxide is taken, dissolved by water and diluted to 1000 mL;
phosphate buffer (ph 5.5): mixing 250mL of 0.2mol/L potassium dihydrogen phosphate solution and 9.0mL of 0.2mol/L sodium hydroxide solution, adding water to dilute to 1000mL, and shaking up to obtain the final product;
phosphate buffer (PH 6.8): mixing 250mL of 0.2mol/L potassium dihydrogen phosphate solution with 112.0mL of 0.2mol/L sodium hydroxide solution, adding water to dilute to 1000mL, and shaking up to obtain the final product;
phosphate buffer (PH 7.2): mixing 250mL of 0.2mol/L potassium dihydrogen phosphate solution and 173.5mL of 0.2mol/L sodium hydroxide solution, adding water to dilute to 1000mL, and shaking up to obtain the final product.
In vitro dissolution test method:
(1) test solution:
taking samples under each embodiment, according to a third method of 0931 dissolution and release determination method in the general rule of the four parts of the Chinese pharmacopoeia 2015 edition, taking 200mL of phosphate buffer solution with pH6.8 as a dissolution medium to perform dissolution test, wherein the temperature is 37 ℃, the rotating speed is 50 r/min, 10mL of sample is taken at 15 min, and the sample is filtered through a 0.45 mu m filter membrane to be used as a test solution;
taking samples under each embodiment, according to a third method of 0931 dissolution and release determination method of the general rule of the four parts of the Chinese pharmacopoeia 2015 edition, taking 200mL of phosphate buffer solution with pH7.2 as a dissolution medium to perform dissolution test, wherein the temperature is 37 ℃, the rotating speed is 75 r/min, 10mL of the sample is taken at 30 min, and the sample is filtered through a 0.45 mu m filter membrane to be used as a test solution;
taking samples under each embodiment, according to a third method of 0931 dissolution and release determination method in the general rule of the four parts of the Chinese pharmacopoeia 2015 edition, taking 200mL of purified water as a dissolution medium to perform a dissolution test, taking 10mL of purified water at 37 ℃ at a rotation speed of 50 rpm for 15 minutes, filtering the sample through a 0.45 mu m filter membrane to serve as a sample solution, supplementing 10mL of purified water, taking 10mL of purified water again at 30 minutes, and filtering the sample through a 0.45 mu m filter membrane to serve as a sample solution;
taking samples under each embodiment, according to a third method of 0931 dissolution and release determination method of the general rule of the four parts of the Chinese pharmacopoeia 2015 edition, taking 200mL of phosphate buffer solution with pH5.5 as a dissolution medium to perform dissolution test, wherein the temperature is 37 ℃, the rotating speed is 100 r/min, 10mL of samples are taken at 30 min, and the samples are filtered through a 0.45 mu m filter membrane to be used as a test solution;
taking samples of each example, the four-generation folic acid tablets are tested for dissolution by taking 200mL of hydrochloric acid solution with pH of 1.2 as a dissolution medium according to a third method of 0931 dissolution and release determination method in the general rules of the four parts of the Chinese pharmacopoeia 2015 edition, rotating at 100 rpm for 30 minutes, sampling 10mL, and passing through a 0.45 μm filter membrane to be used as a test solution.
(2) Control solution:
weighing a certain amount of (6S) -5-methyltetrahydrofolate calcium salt standard (equivalent to 0.020g of (6S) -5-methyltetrahydrofolate), precisely weighing, placing in a 100mL volumetric flask, adding purified water to dissolve and dilute to a scale, carrying out ultrasonic treatment at low temperature for 2min, shaking up, and passing through a 0.45 mu m filter membrane to serve as a control solution.
(3) Measurement method
Chromatographic conditions
The adaptive tailing factor of the system is less than or equal to 2, and the theoretical plate number is more than or equal to 20000.
The determination method comprises injecting water (without solute) according to the above chromatographic conditions, operating the chromatograph according to the above time, analyzing the sample solution and the reference solution respectively, recording the chromatographic peaks of the reference solution and the sample solution, and calculating the dissolution rate (%).
Example 1
The formula is as follows:
| (6S) -5-methyltetrahydrofolic acid, glucosamine salts | 0.1％ | 0.1g |
| Diluent | 94.0％ | Silicified microcrystalline cellulose 94.0g |
| Disintegrating agent | 3.0％ | Crospovidone 3.0g |
| Lubricant agent | 2.9％ | Polyethylene glycol 2.9g |
The preparation method comprises the following steps: weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 5 minutes, adding a lubricant, and mixing for 3 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 80N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.3 percent |
| pH7.2 phosphate buffer | 30 minutes: 95.1 percent |
| Purified water | 15 minutes: 88.5%, 30 min: 98.9 percent |
| pH5.5 phosphate buffer | 30 minutes: 85.2 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 81.0 percent |
Example 2
The formula is as follows:
| (6S) -5-methyltetrahydrofolic acid, glucosamine salts | 15.0％ | 15.0g |
| Diluent | 40.0％ | Pregelatinized starch 20g, microcrystalline cellulose 20.0g |
| Disintegrating agent | 42.0％ | Hydroxypropyl cellulose 2.0g, carboxymethyl starch sodium 40.0g |
| Lubricant agent | 3.0％ | 0.5g of talcum powder and 2.5g of silicon dioxide |
The preparation method comprises the following steps:
(1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 90 minutes, adding a lubricant, and mixing for 60 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 200N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 87.8 percent |
| pH7.2 phosphate buffer | 30 minutes: 97.4 percent |
| Purified water | 15 minutes: 89.2%, 30 minutes: 99.6 percent |
| pH5.5 phosphate buffer | 30 minutes: 90.1 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 89.7 percent |
Example 3
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 48 minutes, adding a lubricant, and mixing for 33 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 140N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 90.2 percent |
| pH7.2 phosphate buffer | 30 minutes: 97.2 percent |
| Purified water | 15 minutes: 90.5%, 30 minutes: 100.2 percent |
| pH5.5 phosphate buffer | 30 minutes: 87.4 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 89.0 percent |
Example 4
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 5 minutes, adding a lubricant, and mixing for 3 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 140N, coating a film coat, and increasing the weight of the coat by 2 percent to obtain the fourth-generation folic acid tablet.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 90.4 percent |
| pH7.2 phosphate buffer | 30 minutes: 93.5 percent |
| Purified water | 15 minutes: 90.7%, 30 minutes: 99.7 percent |
| pH5.5 phosphate buffer | 30 minutes: 88.7 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 84.2 percent of |
Example 5
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 90 minutes, adding a lubricant, and mixing for 60 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 80N, coating a film coat, and increasing the weight of the coat by 6 percent to obtain the fourth-generation folic acid tablet.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.6 percent |
| pH7.2 phosphate buffer | 30 minutes: 92.9 percent |
| Purified water | 15 minutes: 89.7%, 30 minutes: 100.4 percent |
| pH5.5 phosphate buffer | 30 minutes: 89.8 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 87.0 percent |
Example 6
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 48 minutes, adding a lubricant, and mixing for 30 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 200N, coating a film coat, and increasing the weight of the coat by 4 percent to obtain the fourth-generation folic acid tablet.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.2 percent |
| pH7.2 phosphate buffer | 30 minutes: 94.3 percent |
| Purified water | 15 minutes: 89.9%, 30 minutes: 99.8 percent |
| pH5.5 phosphate buffer | 30 minutes: 88.7 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 86.4 percent |
Example 7
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 15 minutes, adding a lubricant, and mixing for 15 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, coating a film coat, and increasing the weight of the coat by 3 percent to obtain the fourth-generation folic acid tablet.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.1 percent |
| pH7.2 phosphate buffer | 30 minutes: 93.8 percent |
| Purified water | 15 minutes: 89.6%, 30 minutes: 100.2 percent |
| pH5.5 phosphate buffer | 30 minutes: 87.9 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 86.7 percent |
Example 8
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 10 minutes, adding a lubricant, and mixing for 20 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.9 percent |
| pH7.2 phosphate buffer | 30 minutes: 94.7 percent |
| Purified water | 15 minutes: 90.3%, 30 minutes: 99.9 percent |
| pH5.5 phosphate buffer | 30 minutes: 89.2 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 86.7 percent |
Example 9
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 15 minutes, adding a lubricant, and mixing for 30 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 89.8 percent |
| pH7.2 phosphate buffer | 30 minutes: 94.7 percent |
| Purified water | 15 minutes: 89.9%, 30 minutes: 100.1 percent |
| pH5.5 phosphate buffer | 30 minutes: 88.6 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 86.9 percent |
Example 10
The formula is as follows:
| (6S) -5-methyltetrahydrofolic acid, glucosamine salts | 0.4％ | 0.4g |
| Diluent | 84.6％ | Calcium hydrogen phosphate 84.6g |
| Disintegrating agent | 2.0％ | Sodium carboxymethyl starch 2.0g |
| Lubricant agent | 13％ | Magnesium stearate 12.0g, polyethylene glycol 1.0g |
The preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 15 minutes, adding a lubricant, and mixing for 30 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 59.3 percent of |
| pH7.2 phosphate buffer | 30 minutes: 62.2 percent |
| Purified water | 15 minutes: 49.4%, 30 min: 70.3 percent of |
| pH5.5 phosphate buffer | 30 minutes: 48.1 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 42.8 percent |
Example 11
The formula is as follows:
the preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 10 minutes, adding a lubricant, and mixing for 20 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 57.2 percent |
| pH7.2 phosphate buffer | 30 minutes: 58.1 percent |
| Purified water | 15 minutes: 36.7%, 30 minutes: 65.4 percent |
| pH5.5 phosphate buffer | 30 minutes: 46.7 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 38.2 percent of |
Example 12
The formula is as follows:
| (6S) -5-methyltetrahydrofolic acid, glucosamine salts | 0.4％ | 0.4g |
| Diluent | 95.0％ | Dextrin 95.0g |
| Disintegrating agent | 4.0％ | Sodium carboxymethyl starch 4.0g |
| Lubricant agent | 0.6％ | Silica 0.6g |
The preparation method comprises the following steps: (1) weighing the following components in percentage by weight:
(2) putting (6S) -5-methyltetrahydrofolic acid, glucosamine salt, a diluent and a disintegrating agent into a mixer, mixing for 15 minutes, adding a lubricant, and mixing for 30 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablet to be 100N, and obtaining the tetra-folic acid tablet without coating.
Dissolution in vitro results:
| dissolution media | Dissolution rate in vitro |
| pH6.8 phosphate buffer | 15 minutes: 49.8 percent |
| pH7.2 phosphate buffer | 30 minutes: 52.3 percent |
| Purified water | 15 minutes: 33.5%, 30 minutes: 62.7 percent |
| pH5.5 phosphate buffer | 30 minutes: 41.5 percent |
| Hydrochloric acid solution of pH1.2 | 30 minutes: 35.2 percent of |
Test example 1 Observation of tear secretion in Dry eye nude mouse
1. Sample source: samples of example 9, example 11 and commercially available folic acid tablets were taken.
2. The test method comprises the following steps: 50 nude mice were selected and randomly divided into a blank group, a model group, an example 9 group, an example 11 group and a commercial sample control group.
The blank group was not treated and normal feed was given daily until the end of the experiment;
the model group is added with 1.5 percent atropine sulfate eye drops which are dropped into eyes three times a day, once in the morning, at noon and at night, and then is given with normal feed every day until the experiment is finished;
example 9 groups were eyed three times a day, once in the morning, at night, with 1.5% atropine sulfate eye drops, starting on day 7 with the addition of the sample of example 9 (equivalent to 100 μ g of (6S) -5-methyltetrahydrofolate) to the feed, until the end of the experiment;
example 11 groups were eyed three times a day, once in the morning, at night, with 1.5% atropine sulfate eye drops, starting on day 7 with the addition of the sample of example 11 (equivalent to 100 μ g of (6S) -5-methyltetrahydrofolate) to the feed, until the end of the experiment;
commercial sample control group was eyed three times a day, once in the morning, at night, with 1.5% atropine sulfate eye drops, starting on day 7 with the addition of commercial sample (equivalent to 100 ug folic acid) to the feed, until the end of the experiment.
Schirmer I tests were performed on days 1, 7 and 30: one end of the tear detection filter paper strip is folded and placed in 1/3 conjunctival sac in the lower eyelid, the filter paper is taken out after 5min, and the wet length of the filter paper is measured from the folding position.
3. Evaluation results were as follows: the invention can promote the tear secretion of the dry eye nude mouse. Specific results are shown in table 1.
TABLE 1 tear volume evaluation results (x. + -. s, mm)
Test example 2 rat in vivo absorption test
1. Sample source: samples of example 2, example 8, example 10 and commercially available folic acid tablets were taken.
2. The test method comprises the following steps: 24 nude mice were collected and randomly divided into example 2 group, example 8 group, example 10 group and commercial sample control group. The group of example 2, the group of example 8 and the group of example 10 were administered by gavage (0.1mg/kg (6S) -5-methyltetrahydrofolic acid) and the group of the commercially available sample control group was administered by gavage (0.1mg/kg folic acid) and fasted without restriction of drinking water after administration.
Blood sampling points: 0h before administration and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration. Whole blood samples were collected from the retro-orbital venous plexus of SD rats. And (3) carrying out folic acid content detection on samples of each sampling time point of each tested animal group by adopting a commercially available rat folic acid ELISA kit, and calculating the mean value of each evaluation item of each tested rat group. And before the sample is analyzed and detected, methodology verification is carried out on the precision, accuracy, specificity, detection limit and the like of the method, and the result shows that the method is accurate and reliable. 3. Evaluation results were as follows: the invention has faster absorption speed and shorter Tmax time. The specific results are shown in Table 2.
TABLE 2 evaluation results of absorption in rats
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (2)
1. A four-generation folic acid tablet, it is made up of (6S) -5-methyltetrahydrofolate glucosamine, thinner, disintegrating agent, lubricant, characterized by that, said four-generation folic acid tablet is according to Chinese pharmacopoeia 2015 edition four parts general rule "0931 dissolution rate and third method of the determination method of release rate", regard pH6.8 phosphate buffer 200ml as dissolution medium to carry on dissolution rate test, the temperature is 37 degrees C, the rotational speed is 50 rounds/minute, dissolution rate is not lower than 85% in vitro in 15 minutes;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH7.2 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 75 r/min, and the dissolution rate in vitro is not lower than 81% in 30 minutes;
according to a third method of 0931 dissolution and release determination in the four general rules of the national pharmacopoeia 2015 edition, the dissolution test is carried out by taking 200ml of purified water as a dissolution medium, the temperature is 37 ℃, the rotating speed is 50 r/min, the 15-minute in-vitro dissolution rate is not lower than 86%, and the 30-minute in-vitro dissolution rate is not lower than 95%;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH5.5 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 70% in 30 minutes;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 edition of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of hydrochloric acid solution with pH1.2 as a dissolution medium, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 60% in 30 min;
the four-generation folic acid tablet comprises: 0.4g of (6S) -5-methyltetrahydrofolate glucosamine salt, 20.0g of pregelatinized starch, 60.0g of microcrystalline cellulose, 6.0g of calcium hydrophosphate, 4.0g of sodium carboxymethyl starch, 4.0g of crospovidone, 4.0g of low-substituted hydroxypropyl cellulose, 1.0g of silicon dioxide and 0.6g of polyethylene glycol; the pregelatinized starch, the microcrystalline cellulose and calcium hydrogen phosphate constitute the diluent, the sodium carboxymethyl starch, the crospovidone and the low-substituted hydroxypropyl cellulose constitute the disintegrant, and the silicon dioxide and the polyethylene glycol constitute the lubricant;
the preparation method of the four-generation folic acid tablet comprises the following steps:
(1) weighing the (6S) -5-methyltetrahydrofolate glucosamine salt, the diluent, the disintegrant and the lubricant according to the weight components for later use;
(2) placing the (6S) -5-methyltetrahydrofolate glucosamine salt, the diluent and the disintegrant in a mixer, mixing for 5-90 minutes, adding the lubricant, and mixing for 3-60 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablets to be 80-200N, and coating or not coating to obtain the tetrahydrofolic acid tablets.
2. A four-generation folic acid tablet, it is made up of (6S) -5-methyltetrahydrofolate glucosamine, thinner, disintegrating agent, lubricant, characterized by that, said four-generation folic acid tablet is according to Chinese pharmacopoeia 2015 edition four parts general rule "0931 dissolution rate and third method of the determination method of release rate", regard pH6.8 phosphate buffer 200ml as dissolution medium to carry on dissolution rate test, the temperature is 37 degrees C, the rotational speed is 50 rounds/minute, dissolution rate is not lower than 85% in vitro in 15 minutes;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH7.2 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 75 r/min, and the dissolution rate in vitro is not lower than 81% in 30 minutes;
according to a third method of 0931 dissolution and release determination in the four general rules of the national pharmacopoeia 2015 edition, the dissolution test is carried out by taking 200ml of purified water as a dissolution medium, the temperature is 37 ℃, the rotating speed is 50 r/min, the 15-minute in-vitro dissolution rate is not lower than 86%, and the 30-minute in-vitro dissolution rate is not lower than 95%;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 version of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of phosphate buffer solution with pH5.5 as a dissolution medium, the temperature is 37 ℃, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 71% in 30 minutes;
according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the 2015 edition of Chinese pharmacopoeia, the dissolution test is carried out by taking 200ml of hydrochloric acid solution with pH1.2 as a dissolution medium, the rotating speed is 100 r/min, and the dissolution rate in vitro is not lower than 62% in 30 min;
the four-generation folic acid tablet comprises: 0.9g of (6S) -5-methyltetrahydrofolate glucosamine salt, 80.0g of microcrystalline cellulose, 7.0g of sodium carboxymethyl starch, 11.0g of crospovidone and 1.1g of silicon dioxide; the microcrystalline cellulose constitutes the diluent, the sodium carboxymethyl starch and the crospovidone constitute the disintegrant, and the silicon dioxide constitutes the lubricant;
the preparation method of the four-generation folic acid tablet comprises the following steps:
(1) weighing the (6S) -5-methyltetrahydrofolate glucosamine salt, the diluent, the disintegrant and the lubricant according to the weight components for later use;
(2) placing the (6S) -5-methyltetrahydrofolate glucosamine salt, the diluent and the disintegrant in a mixer, mixing for 5-90 minutes, adding the lubricant, and mixing for 3-60 minutes for later use;
(3) and (3) putting the materials in the step (2) into a tablet machine, tabletting, controlling the hardness of the tablets to be 80-200N, and coating or not coating to obtain the tetrahydrofolic acid tablets.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813656A (en) * | 2012-09-13 | 2012-12-12 | 广东岭南制药有限公司 | Stable medicine composition of 5-methyltetrahydrofolic acid or salt thereof |
| CN103450202A (en) * | 2012-06-04 | 2013-12-18 | 南京莱因医药科技有限公司 | Method for reacting L-5-methyltetrahydrofolic acid with organic base to form salt |
| US20150050261A1 (en) * | 2013-08-16 | 2015-02-19 | Vertical Pharmaceuticals, Llc | Dietary and nutritional supplements containing an omega-3 fatty acid of plant-based origin and a folate derivative |
| CN105030779A (en) * | 2015-07-21 | 2015-11-11 | 福格森（武汉）生物科技股份有限公司 | (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and method for preparing same |
| CN105524066A (en) * | 2014-09-04 | 2016-04-27 | 连云港金康和信药业有限公司 | (6S)-5-methyltetrahydrofolic acid or (6S)-5-methyltetrahydrofolate composition and preparation method and use thereof |
| CN107028950A (en) * | 2016-02-03 | 2017-08-11 | 常州爱诺新睿医药技术有限公司 | A kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| US10039805B1 (en) * | 2016-02-26 | 2018-08-07 | Michelle Ann Toothman | Infant formulas having vitamin complexes with enhanced bioavailability |
-
2018
- 2018-08-19 CN CN201810944848.8A patent/CN108926544B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450202A (en) * | 2012-06-04 | 2013-12-18 | 南京莱因医药科技有限公司 | Method for reacting L-5-methyltetrahydrofolic acid with organic base to form salt |
| CN102813656A (en) * | 2012-09-13 | 2012-12-12 | 广东岭南制药有限公司 | Stable medicine composition of 5-methyltetrahydrofolic acid or salt thereof |
| US20150050261A1 (en) * | 2013-08-16 | 2015-02-19 | Vertical Pharmaceuticals, Llc | Dietary and nutritional supplements containing an omega-3 fatty acid of plant-based origin and a folate derivative |
| CN105524066A (en) * | 2014-09-04 | 2016-04-27 | 连云港金康和信药业有限公司 | (6S)-5-methyltetrahydrofolic acid or (6S)-5-methyltetrahydrofolate composition and preparation method and use thereof |
| CN105030779A (en) * | 2015-07-21 | 2015-11-11 | 福格森（武汉）生物科技股份有限公司 | (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and method for preparing same |
| CN107028950A (en) * | 2016-02-03 | 2017-08-11 | 常州爱诺新睿医药技术有限公司 | A kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| US10039805B1 (en) * | 2016-02-26 | 2018-08-07 | Michelle Ann Toothman | Infant formulas having vitamin complexes with enhanced bioavailability |
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