CN114983954A - Folic acid tablet and preparation method thereof - Google Patents
Folic acid tablet and preparation method thereof Download PDFInfo
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- CN114983954A CN114983954A CN202210681656.9A CN202210681656A CN114983954A CN 114983954 A CN114983954 A CN 114983954A CN 202210681656 A CN202210681656 A CN 202210681656A CN 114983954 A CN114983954 A CN 114983954A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
Abstract
The invention relates to a folic acid tablet and a preparation method thereof. The folic acid tablet comprises the following raw materials in percentage by weight: 0.3 to 0.35 percent of folic acid, 1.3 to 4.8 percent of micro silica gel powder, 0.3 to 1.5 percent of lubricant and 100 percent of excipient; the preparation method of the folic acid tablet comprises the following steps: (1) repeatedly mixing folic acid and micro silica gel according to the dosage proportion of 4-15 times to completely wrap folic acid by the micro silica gel to obtain a folic acid wrap; (2) uniformly mixing the folic acid wrappage and part of excipient to obtain medicine-containing mixed powder; (3) mixing the rest excipients uniformly to obtain auxiliary material mixed powder; (4) and uniformly mixing the medicine-containing mixed powder and the auxiliary material mixed powder, adding the lubricant, continuously and uniformly mixing, and performing powder direct pressing to obtain the folic acid tablets. The folic acid tablet prepared by the method has low impurity content and good stability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to folic acid tablets and a preparation method thereof.
Background
Folic acid, also known as vitamin M and vitamin Bc, is a generic name for a group of compounds with similar chemical structures and similar biochemical characteristics, and is formed by combining pteroic acid, p-aminobenzoic acid and 1 or more glutamic acids. The chemical name of the L-glutamic acid is N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino ] benzoyl ] L-glutamic acid, and the L-glutamic acid is commonly called pteroylglutamic acid.
Folic acid is involved in the biosynthesis of nucleic acids, proteins, etc. in vivo and, therefore, plays an important role in cell proliferation: folic acid cannot be released during embryo development of a fetus, hyperplasia of various cells in an infant stage, and hyperplasia of erythrocytes, leukocytes, intestinal mucosa cells and the like of other people. The deficiency of folic acid can cause diseases such as anemia, chronic diseases, hypoevolutism, leukopenia and the like, and the deficiency of folic acid in pregnant women can cause the occurrence of neural tube malformation. For pregnant women with large folic acid demand or other people with insufficient folic acid intake, the folic acid tablet is an effective way for supplementing folic acid.
Folic acid is sensitive to light and unstable under high temperature and high humidity conditions, and factors such as humidity, heat and light have great influence on the stability of folic acid preparations in the preparation process of folic acid tablets. Therefore, in the preparation process of the folic acid tablets, how to solve the influence of factors such as humidity and heat on the stability of the folic acid is solved, and the improvement of the storage stability of the folic acid tablets is the key to control the quality of the folic acid tablets.
Disclosure of Invention
Accordingly, an object of the present invention is to provide a method for producing folic acid tablets, which are low in impurity content and excellent in stability.
In order to achieve the purpose, the invention comprises the following technical scheme.
A preparation method of folic acid tablets comprises the following raw materials in percentage by weight:
the mass ratio of the folic acid to the micro-powder silica gel is 1: 4-15;
the preparation method comprises the following steps:
(1) mixing folic acid and silica gel micropowder repeatedly to completely wrap folic acid with silica gel micropowder to obtain folic acid wrap;
(2) uniformly mixing the folic acid wrappage and part of excipient to obtain medicine-containing mixed powder;
(3) mixing the rest excipients uniformly to obtain auxiliary material mixed powder;
(4) and uniformly mixing the medicine-containing mixed powder and the auxiliary material mixed powder, adding the lubricant, continuously and uniformly mixing, and performing powder direct pressing to obtain the folic acid tablets.
In some of these embodiments, the excipient is selected from a composition of two or more of microcrystalline cellulose, starch, and lactose spray; the starch is selected from at least one of pregelatinized starch, direct-pressed starch and super-flowing starch.
In some of these embodiments, the excipients consist of microcrystalline cellulose, starch, and lactose spray.
In some of these embodiments, the excipient is formed from a mixture of, by mass, 1: 0.5-0.7: 1.8-2.5 parts of microcrystalline cellulose, starch and spray lactose; the starch is pregelatinized starch or direct-pressure starch.
In some of these embodiments, the lubricant is selected from at least one of talc, colloidal silicon dioxide, magnesium stearate, and sodium fumarate.
In some embodiments, the folic acid tablet comprises the following raw materials in percentage by weight:
in some embodiments, the folic acid tablet comprises the following raw materials in percentage by weight:
in some of these embodiments, the method of making the folic acid tablet comprises the steps of:
(1) respectively crushing folic acid and micro silica gel powder, sieving the crushed folic acid and the micro silica gel powder by a 150-mesh sieve, repeatedly mixing the materials to ensure that the folic acid is completely wrapped by the micro silica gel powder, and sieving the materials by a 120-mesh sieve for 5-7 times to obtain a folic acid wrapping object;
(2) sieving the excipient by a sieve of 80-120 meshes, then uniformly mixing the folic acid wrappage and part of sieved excipient, and sieving for 5 times by the sieve of 80 meshes to obtain medicine-containing mixed powder;
(3) mixing the rest excipients sieved by the 80-120-mesh sieve for 8-12 minutes, and sieving by the 80-mesh sieve for 2 times to obtain auxiliary material mixed powder;
(4) and mixing the medicine-containing mixed powder and the auxiliary material mixed powder for 3-10 minutes, adding the lubricant, continuously mixing for 2-5 minutes, and performing powder direct pressing to obtain the folic acid tablets.
In some of these embodiments, the process parameters of the direct powder pressing include: the technological parameters of the powder direct pressing are as follows: the rotating speed of the powder servo device is 20-35 rpm, the rotating speed of the central disc is 90-140 rpm, the production speed is 54-84 KT/H, the weight of the tablet is 125 +/-0.5 mg, the weight difference is +/-5.0%, the thickness of the tablet is 3.27 +/-0.05 mm, the hardness is 2-4 kg, the main pressure is 8-10.5 KN, and the pre-pressure is 6-8 KN
Compared with the prior art, the invention has the following beneficial effects:
the inventor of the invention finds that folic acid tablets with low impurity content and good drug stability can be prepared by repeatedly mixing folic acid and aerosil according to the dosage proportion of 4-15 times to ensure that folic acid is completely wrapped by aerosil to form a folic acid wrapping object, and then matching excipient with good compressibility and a preparation process of powder direct compression.
The folic acid raw material medicine is completely wrapped by the micropowder silica gel, so that the folic acid of the main drug can be effectively protected, and the folic acid is not easily influenced by high humidity, high temperature and light in the preparation process, thereby improving the stability of the main drug. The inventor proves that the folic acid raw material can be protected to a greater extent after the micro-powder silica gel and the folic acid as the main drug are mixed and wrapped, and the stability of the folic acid as the main drug is ensured through a plurality of experiments, so that the impurity content of the folic acid tablet is greatly reduced, and the stability is greatly improved.
Furthermore, the excipient with good compressibility is selected, so that the main pressure in the tabletting process is reduced, impurities can be further reduced, and the stability of folic acid is improved. The hardness of the sheet extruded under relatively low pressure is relatively high, so that the brightness of the sheet surface is ensured, and the sheet is not scribed in the aluminum-plastic packaging process. Since the degradation impurities of folic acid tablets are inversely proportional to the main pressure, the lower the pressure the lower the degradation impurities.
In addition, compared with a sample prepared by wet granulation, the folic acid tablet prepared by the powder direct compression process has the comprehensive advantages of less related substances, controllable quality, simple preparation process, less energy consumption, no environmental pollution, greatly reduced production cost and easiness in batch production. Folic acid is relatively sensitive to humidity and heat, water is required to be added for granulation and drying in the wet granulation process, impurities are obviously increased, and the product quality is affected; and the wet granulation process has multiple steps, high energy consumption, poor continuous production capacity and poor process reproducibility. The sample (comparative example 1) using the wet granulation process showed a significant increase in impurity a and total impurities after 10 days of high temperature and 10 days of light exposure, far above the commercial formulation. The preparation method of the invention effectively solves the defects of wet granulation, can effectively reduce the impurities of the prepared folic acid tablets, and improves the stability of the folic acid tablets.
The quality of the folic acid tablets finally obtained is greatly improved by selecting the specific auxiliary materials and combining the specific preparation process, the related substances are obviously reduced, the impurity content is obviously reduced, and the preparation has good stability and is superior to the corresponding commercially available preparation.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
The following are specific examples.
Example 1
The formulation of folic acid tablets provided in this example is shown in table 1 below:
TABLE 1
And (4) converting the sample feeding amount of the folic acid according to the actually measured content and the moisture. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but since the weight of folic acid contained in the raw material was 0.4mg, the weight ratio of folic acid contained in the folic acid tablets was 0.32%.
The preparation method of the folic acid tablet provided by the embodiment comprises the following steps:
1) respectively crushing the folic acid raw material and the micro silica gel powder, sieving the crushed folic acid raw material and the micro silica gel powder with a 150-mesh sieve, repeatedly mixing the crushed folic acid raw material and the micro silica gel powder to enable the folic acid to be completely wrapped by the micro silica gel powder, and then sieving the mixture with a 120-mesh sieve for 6 times to obtain the folic acid wrapping object.
2) Sieving pregelatinized starch, spray lactose and microcrystalline cellulose with 100 mesh sieve;
3) uniformly mixing the folic acid wrappage and part of the screened pregelatinized starch, and screening for 5 times by using a 80-mesh sieve to obtain medicine-containing mixed powder;
4) mixing the sieved lactose, the rest pregelatinized starch and the sieved microcrystalline cellulose for 10 minutes, and sieving with a 80-mesh sieve for 2 times to obtain an auxiliary material mixed powder;
5) adding the medicine-containing mixed powder and the auxiliary material mixed powder into a mixer, mixing for 5 minutes, adding magnesium stearate, continuously mixing for 3 minutes, and tabletting to obtain the folic acid tablets;
the tabletting process comprises the following steps: installing a circular punching die with the diameter of 7.0mm on a ZP10A rotary tablet press, setting the rotating speed of a powder servo device to be 20-35 rpm, the rotating speed of a middle disc to be 90-140 rpm, the production speed to be 54-84 KT/H, the actual tablet weight to be 125 +/-0.5 mg, and the weight difference to be +/-5.0%; the thickness of the sheet is controlled to be 3.27 +/-0.05 mm, and the hardness is controlled to be 2-4 kg; controlling the main pressure to be 8-10.5 KN and the pre-pressure to be 6-8 KN; then, a tablet press starting button is started to start tablet pressing. In the tabletting process, the appearance, the surfaces and the friability of the tablets need to be ensured to meet the requirements, and the phenomena of splintering, loose tablets and burr and corner lacking are avoided. Light shielding is needed in the tabletting process, the temperature is controlled below 26 ℃, and the relative humidity is controlled below 50%.
Example 2:
the formulation of folic acid tablets provided in this example is shown in table 2 below:
TABLE 2
And (4) converting the sample feeding amount of the folic acid according to the actually measured content and the moisture. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but the weight of folic acid contained in the folic acid raw material was 0.4mg, and the weight ratio of folic acid raw material in the folic acid tablet was 0.32%.
The preparation method of the folic acid tablet provided by the embodiment comprises the following steps:
1) respectively crushing the folic acid raw material and the superfine silica powder, sieving by a 150-mesh sieve, repeatedly mixing to completely wrap the folic acid by the superfine silica powder, and sieving by a 120-mesh sieve for 6 times to obtain the folic acid wrap.
2) Sieving the direct-compression starch, the spray lactose and the microcrystalline cellulose with a 100-mesh sieve for later use;
3) uniformly mixing the folic acid wrappage and part of the sieved direct-pressure starch, and sieving the mixture for 5 times by using a 80-mesh sieve to obtain medicine-containing mixed powder;
4) mixing the sieved lactose, residual direct-compression starch and the sieved microcrystalline cellulose for 10 minutes, and sieving for 2 times by a 80-mesh sieve to obtain auxiliary material mixed powder;
5) and adding the medicine-containing mixed powder and the auxiliary material mixed powder into a mixer, mixing for 5 minutes, adding magnesium stearate, continuously mixing for 3 minutes, and tabletting (the specific tabletting process is the same as that in example 1), so as to obtain the folic acid tablets.
Comparative example 1:
the formulation composition of the folic acid tablets provided by this comparative example is shown in table 3 below:
TABLE 3
And converting the sample adding amount of folic acid according to the actually measured content and water content. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but the weight of folic acid contained in the folic acid raw material was 0.4mg, and the weight ratio of folic acid raw material in the folic acid tablet was 0.32%.
The preparation method of the folic acid tablet provided by the comparative example comprises the following steps:
1) crushing the folic acid raw material and sieving the crushed folic acid raw material with a 150-mesh sieve for later use;
2) preparing 5% starch slurry from part of pregelatinized starch and purified water by using a slurry flushing method for later use;
3) premixing the sieved folic acid, the sprayed lactose, the microcrystalline cellulose and the rest pregelatinized starch for 10 minutes, and then slowly adding the starch slurry and stirring to prepare a proper soft material;
4) preparing wet granules after installing a 20-mesh stainless steel net by using a swing granulator;
5) putting the wet granules into a fluidized bed and drying until the water content of the granules is below 3.0%;
6) and (3) granulating the dried qualified granules by using a 18-mesh sieve, adding magnesium stearate, mixing for 3 minutes, and tabletting (the specific tabletting process is the same as that in example 1) to obtain the folic acid tablets.
Comparative example 2
The formulation composition of the folic acid tablets provided by this comparative example is shown in table 4 below:
TABLE 4
And (4) converting the sample feeding amount of the folic acid according to the actually measured content and the moisture. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but the weight of folic acid contained in the folic acid raw material was 0.4mg, and the weight ratio of folic acid raw material in the folic acid tablet was 0.32%.
The preparation method of the folic acid tablet provided by the comparative example comprises the following steps:
1) respectively pulverizing folic acid raw material and glyceryl behenate, sieving with 150 mesh sieve, mixing repeatedly to completely wrap folic acid with glyceryl behenate, and sieving with 120 mesh sieve for 6 times to obtain folic acid wrap.
2) Sieving pregelatinized starch, spray lactose and microcrystalline cellulose with 100 mesh sieve;
3) uniformly mixing the folic acid wrappage and part of the screened pregelatinized starch, and screening for 5 times by using a 80-mesh sieve to obtain medicine-containing mixed powder;
4) mixing the sieved lactose, the rest pregelatinized starch and the sieved microcrystalline cellulose for 10 minutes, and sieving with a 80-mesh sieve for 2 times to obtain an auxiliary material mixed powder;
5) and adding the medicine-containing mixed powder and the auxiliary material mixed powder into a mixer, mixing for 5 minutes, adding magnesium stearate, continuously mixing for 3 minutes, and tabletting (the specific tabletting process is the same as that in example 1) to obtain the folic acid tablets.
Comparative example 3
The formulation composition of the folic acid tablets provided by this comparative example is shown in table 5 below:
TABLE 5
And (4) converting the sample feeding amount of the folic acid according to the actually measured content and the moisture. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but the weight of folic acid contained in the folic acid raw material was 0.4mg, and the weight ratio of folic acid raw material in the folic acid tablet was 0.32%.
The preparation method of the folic acid tablet provided by the comparative example comprises the following steps:
1) respectively crushing the folic acid raw material and polyethylene glycol 4000, sieving the crushed folic acid raw material and the polyethylene glycol 4000 by a 150-mesh sieve, repeatedly mixing the crushed folic acid raw material and the polyethylene glycol 4000 to completely wrap folic acid by the polyethylene glycol 4000, and then sieving the mixture by a 120-mesh sieve for 6 times to obtain the folic acid wrap.
2) Sieving pregelatinized starch, spray lactose and microcrystalline cellulose with 100 mesh sieve;
3) uniformly mixing the folic acid wrappage and part of the screened pregelatinized starch, and screening for 5 times by using a 80-mesh sieve to obtain medicine-containing mixed powder;
4) mixing the sieved lactose, residual pregelatinized starch and sieved microcrystalline cellulose for 10 minutes, and sieving with 80-mesh sieve for 2 times to obtain adjuvant mixed powder;
5) and adding the medicine-containing mixed powder and the auxiliary material mixed powder into a mixer, mixing for 5 minutes, adding magnesium stearate, continuously mixing for 3 minutes, and tabletting (the specific tabletting process is the same as that in example 1), so as to obtain the folic acid tablets.
Comparative example 4
The formulation composition of the folic acid tablets provided by this comparative example is shown in table 6 below:
TABLE 6
And (4) converting the sample feeding amount of the folic acid according to the actually measured content and the moisture. When the content of the raw material medicine is more than or equal to 100%, performing dry-turning calculation according to the content of 100%; when the content is less than 100%, the content is calculated according to the actual content on a dry basis. The actual feeding amount (g) is equal to the theoretical feeding amount (g)/content/(1-loss on drying). Because the content of the folic acid raw material medicine is more than 100%, the drying weight loss of the folic acid raw material medicine is known to be 7.96% according to 100% dry basis, and therefore the feeding amount of the folic acid raw material medicine is converted as follows: 0.4 mg/(1-loss on drying) ═ 0.4 mg/(1-7.96%) -0.4346 mg. That is, the amount of folic acid raw material charged was 0.4346mg, but the weight of folic acid contained in the folic acid raw material was 0.4mg, and the weight ratio of folic acid raw material in the folic acid tablet was 0.32%.
The preparation method of the folic acid tablet provided by the comparative example comprises the following steps:
1) respectively crushing the folic acid raw material and the micro-powder silica gel and sieving the crushed materials with a 150-mesh sieve for later use.
2) Sieving pregelatinized starch, spray lactose and microcrystalline cellulose with 100 mesh sieve;
3) mixing folic acid and part of the sieved pregelatinized starch uniformly, and sieving with 80 mesh sieve for 5 times to obtain medicine-containing mixed powder;
4) mixing the sieved micropowder silica gel and lactose, the rest pregelatinized starch and the sieved microcrystalline cellulose for 10 minutes, and sieving with a 80-mesh sieve for 2 times to obtain adjuvant mixed powder;
5) and adding the medicine-containing mixed powder and the auxiliary material mixed powder into a mixer, mixing for 5 minutes, adding magnesium stearate, continuously mixing for 3 minutes, and tabletting (the specific tabletting process is the same as that in example 1), so as to obtain the folic acid tablets.
Example 3
The folic acid tablets prepared in the examples and the comparative examples were tested for content uniformity according to the content uniformity test method in the folic acid tablet item of the 2020 edition of the Chinese pharmacopoeia, and the results are shown in Table 7.
TABLE 7 detection results of folic acid piece content uniformity
| Detecting items | Average content (%) | Standard deviation S | A+2.2S |
| Example 1 | 99.52 | 1.21 | 3.14 |
| Example 2 | 99.41 | 1.51 | 3.91 |
| Comparative example 1 | 99.35 | 1.94 | 5.53 |
| Comparative example 2 | 99.10 | 2.09 | 5.32 |
| Comparative example 3 | 99.30 | 2.06 | 5.49 |
| Comparative example 4 | 99.22 | 2.04 | 5.46 |
| Commercially available formulations | 99.01 | 2.09 | 5.52 |
The data in Table 7 show that the content uniformity of the folic acid tablets prepared by the invention is obviously better than that of the commercial preparation (Silian: specification 0.4mg, batch number S200608) and the comparative example, and the folic acid tablets prepared according to the prescription and the process of the invention have better quality than the existing commercial preparation.
Example 4
The folic acid tablets prepared in the examples and the comparative examples were tested according to the dissolution rate test method in the item of folic acid tablets in the 'Chinese pharmacopoeia' 2020 edition, and the results are shown in Table 8.
TABLE 8 dissolution test results of folic acid tablets
| Detecting items | Dissolution rate in 15 minutes | Dissolution rate in 30 minutes |
| Example 1 | 88.6％ | 96.8％ |
| Example 2 | 89.8％ | 97.3％ |
| Comparative example 1 | 88.0％ | 93.1％ |
| Comparative example 2 | 85.9％ | 95.9％ |
| Comparative example 3 | 85.9％ | 95.1％ |
| Comparative example 4 | 85.9％ | 94.5％ |
| Commercially available formulations | 82.1％ | 92.9％ |
The data in Table 8 illustrate that folic acid tablets prepared according to the present invention have higher dissolution rates and are higher than the commercial formulation (Silian: Specification 0.4mg, batch No. S200608), suggesting that good in vivo bioavailability is possible.
Example 5 stability study under accelerated conditions
The folic acid tablets prepared in examples and comparative examples were packaged on the market, and were taken out from a commercial preparation (silian: 0.4mg standard, lot S200608) under accelerated conditions (temperature 40 ℃/RH 75%) for 0, 3, and 6 months, and the stability of the folic acid tablets was examined by examining the substances according to the methods for examining the substances under the term of folic acid tablets in the current chinese pharmacopoeia, wherein the impurity a means a degradation impurity (as received in the foreign pharmacopoeia EP6.0/EP 2009). The results are shown in Table 9 below.
TABLE 9 stability test results for folic acid tablets
Note: the pteroic acid is an impurity contained in the bulk drug, and the influence of a specific process of the preparation on the pteroic acid is found to be small in the experimental process, so that the pteroic acid content of each embodiment, each comparative example and each commercially available preparation is equivalent to that of each of the 0 day, the 3 month and the 6 month preparations, and is within the range of 0.23-0.25%.
The data in table 9 show that: after the folic acid tablets prepared in the examples 1-2 are subjected to an acceleration condition for 6 months, the contents of impurity A, maximum unknown impurities and total impurities in related substances are obviously smaller than those of a commercially available preparation and the folic acid tablets prepared in the comparative examples 1-4; moreover, the growth range of each impurity of the folic acid tablets prepared in the examples 1 to 2 is obviously smaller than that of the folic acid tablets of the commercial preparations and the comparative examples 1 to 4.
Example 6 high temperature stability and light stability investigation:
(I) according to influence factor investigation conditions in the traditional Chinese medicine and preparation stability test guiding principle in the appendix of the 2020 edition of Chinese pharmacopoeia, the folic acid tablets without packages are inspected for 10 days at the high temperature of 60 ℃, and the results are shown in Table 10, wherein the commercially available preparation is Silian: specification 0.4mg, batch No. S200608.
TABLE 10 high temperature stability test results
Note: the pteroic acid is an impurity contained in the bulk drug, and the influence of a specific process of the preparation on the pteroic acid is found to be small in the experimental process, so that the pteroic acid content of each embodiment, each comparative example and each commercially available preparation in 0 day and 10 days is equivalent, and is within the range of 0.23-0.25%.
(II) investigating folic acid tablets without packages for 10 days under the illumination condition according to influence factor investigation conditions in the stability test guiding principle of the traditional Chinese medicines and the preparations in the appendix of 'Chinese pharmacopoeia' 2020 edition, wherein the results are shown in Table 11, wherein the commercially available preparation is silian: specification 0.4mg, batch No. S200608.
TABLE 11 photostability examination results
Note: the pteroic acid is an impurity contained in the bulk drug, and the influence of a specific process of the preparation on the pteroic acid is found to be small in the experimental process, so that the pteroic acid content of each embodiment, each comparative example and each commercially available preparation in 0 day and 10 days is equivalent, and is within the range of 0.23-0.25%.
From the data of tables 10 and 11, it can be seen that: the folic acid tablets prepared in the examples 1-2 are proved to have good preparation stability through high-temperature tests and illumination tests of influence factors, the pteroic acid is almost unchanged, and the increase range of the impurity A and the total impurity content is smaller after 10 days than that of the folic acid tablets after 0 day; the single impurity and total impurity of the preparation sold in the market are increased to a larger extent, which shows that the quality of the folic acid tablet prepared by the invention is obviously improved and the stability is better than that of the existing products sold in the market.
In comparative example 1 (adopting a wet granulation process), the impurity a and the total impurities are significantly increased after 10 days of high temperature and 10 days of light irradiation, and are higher than those of the commercially available preparation; compared example 2 (adopting behenate glyceride as a stabilizer) and compared example 3 (adopting polyethylene glycol 4000 as a stabilizer) obviously increase the impurity A and the total impurity after 10 days of high temperature and 10 days of illumination; in comparative example 4 (the process of completely wrapping folic acid by using the stabilizer-aerosil determined by the invention is not adopted), the impurity A and the total impurities are obviously increased after 10 days of high temperature and 10 days of illumination.
The above data show that the stability of the obtained folic acid tablets can be effectively improved by combining the specific formula and the preparation process of the invention.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The preparation method of the folic acid tablet is characterized in that the folic acid tablet comprises the following raw materials in percentage by weight:
the mass ratio of the folic acid to the micro-powder silica gel is 1: 4-15;
the preparation method of the folic acid tablet comprises the following steps:
(1) repeatedly mixing folic acid and aerosil to completely wrap folic acid by the aerosil to obtain folic acid wrap;
(2) uniformly mixing the folic acid wrappage and part of excipient to obtain medicine-containing mixed powder;
(3) mixing the rest excipients uniformly to obtain auxiliary material mixed powder;
(4) and uniformly mixing the medicine-containing mixed powder and the auxiliary material mixed powder, adding the lubricant, continuously and uniformly mixing, and performing powder direct pressing to obtain the folic acid tablets.
2. The method for preparing folic acid tablets according to claim 1, wherein the excipient is a composition of two or more selected from the group consisting of microcrystalline cellulose, starch, and lactose spray; the starch is selected from at least one of pregelatinized starch, direct compression starch and super-flow starch.
3. The process for the preparation of folic acid tablets according to claim 2, characterized in that the excipients consist of microcrystalline cellulose, starch and lactose spray.
4. The method for preparing folic acid tablets according to claim 3, wherein the excipient consists of the following components in a mass ratio of 1: 0.5-0.7: 1.8-2.5 of microcrystalline cellulose, starch and spray lactose; the starch is pregelatinized starch or direct-compression starch.
5. The process for preparing folic acid tablets according to claim 1, wherein the lubricant is at least one selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and sodium fumarate.
6. The method for preparing folic acid tablets according to claim 1, characterized in that the raw materials of the folic acid tablets comprise the following components in percentage by weight:
7. the method for preparing folic acid tablets according to claim 6, characterized in that the raw materials of the folic acid tablets comprise the following components in percentage by weight:
8. the method for preparing folic acid tablets according to any one of claims 1 to 7, characterized by comprising the following steps:
(1) respectively crushing folic acid and aerosil, sieving the crushed folic acid and the aerosil through a 150-mesh sieve, repeatedly mixing the crushed folic acid and the aerosil to completely wrap the folic acid by the aerosil, and sieving the mixture for 5-7 times through a 120-mesh sieve to obtain folic acid wrappage;
(2) sieving the excipient by a sieve of 80-120 meshes, then uniformly mixing the folic acid wrappage and part of sieved excipient, and sieving by a sieve of 80 meshes for 5 times to obtain medicine-containing mixed powder;
(3) mixing the rest excipients sieved by the 80-120-mesh sieve for 8-12 minutes, and sieving by the 80-mesh sieve for 2 times to obtain auxiliary material mixed powder;
(4) and mixing the medicine-containing mixed powder and the auxiliary material mixed powder for 3-10 minutes, adding the lubricant, continuously mixing for 2-5 minutes, and performing powder direct pressing to obtain the folic acid tablets.
9. The method for preparing folic acid tablets according to any one of claims 1 to 7, wherein the process parameters of the powder direct pressing comprise: the rotating speed of the powder servo device is 20-35 rpm, the rotating speed of the middle disc is 90-140 rpm, the production speed is 54-84 KT/H, the weight of the tablet is 125 +/-0.5 mg, the weight difference is +/-5.0%, the thickness of the tablet is 3.27 +/-0.05 mm, the hardness is 2-4 kg, the main pressure is 8-10.5 KN, and the pre-pressure is 6-8 KN.
10. A folic acid tablet produced by the production method according to any one of claims 1 to 9.
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