CN115040489A - Stable pharmaceutical composition with excellent consistency and process for preparing the same - Google Patents
Stable pharmaceutical composition with excellent consistency and process for preparing the same Download PDFInfo
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- 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
- 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
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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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
The present invention relates to a stable pharmaceutical composition with excellent consistency and a preparation method thereof. In particular to a folic acid tablet which comprises the following components in percentage by weight: 0.4 part of folic acid, 1.5-2.5 parts of fatty acid compound, 4-6 parts of cellulose, 10-15% of disintegrant and 80-250 mg of lactose. The invention also relates to a method for preparing the folic acid tablet and application of the folic acid tablet in preparing medicaments for preventing congenital neural tube malformation of fetuses, preventing women in pregnancy and lactation and the like. The tablet pharmaceutical composition of the present invention, which uses folic acid as an active ingredient, has excellent process and performance consistency under a wide range of dosage design conditions, and exhibits excellent physical and chemical stability.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition, in particular to a pharmaceutical composition taking folic acid as an active ingredient, which has excellent process and performance consistency under wide dosage design conditions and has excellent physical and chemical stability.
Background
Folic Acid, N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino]Benzoyl radical]-L-glutamic acid of formula C 19 H 19 N 7 O 6 Molecular weight 441.40, having the following chemical formula:
folic acid, also known as vitamin B9, is a member of the B group of vitamins and is also an essential cofactor for enzymes involved in DNA and RNA synthesis. Since humans are unable to endogenously synthesize folic acid, deficiency must be prevented by diet and supplementation. Folic acid is present in green vegetables, legumes and some fruits. Inadequate levels of folate can lead to a number of health problems, including cardiovascular disease, megaloblastic anemia, cognitive deficits, and Neural Tube Defects (NTDs). For example, women are often supplemented with folic acid during pregnancy to prevent the development of NTD, and alcoholics are supplemented with folic acid to prevent the development of neurological disorders.
The broad-sense folic acid is a water-soluble vitamin, which is named because the green leaves are rich in pteroylglutamic acid. There are several existing forms in nature, and the parent compound is made up by combining 3 components of pteridine, p-aminobenzoic acid and glutamic acid. Folic acid contains 1 or more glutamyl groups and most naturally occurring folic acid is in the form of polyglutamic acid. The biologically active form of folic acid is tetrahydrofolic acid. Folic acid is yellow crystals, slightly soluble in water, but its sodium salt is very soluble in water. Is insoluble in ethanol. It is easily destroyed in acid solution, unstable to heat, easily lost at room temperature, and easily destroyed by visible light. Folic acid has two modes of active absorption and diffusion passive absorption in vivo, and the absorption part is mainly on the upper part of the small intestine. The absorption rate of reduced folic acid is higher, the more glutamyl, the lower the absorption rate, and glucose and vitamin C can promote absorption. The folic acid after absorption is present in tissues such as intestinal wall, liver, and bone marrow in vivo, and is reduced by folate reductase in the presence of NADPH to tetrahydrofolic acid (THFA or FH4) having physiological activity, which is involved in the synthesis of purine and pyrimidine. Therefore, folic acid plays an important role in the processes of protein synthesis, cell division and growth and has a promoting effect on the formation of normal red blood cells. The deficiency can cause the reduction of hemoglobin production in erythrocytes and the obstruction of cell maturation, resulting in megaloblastic anemia.
Folic acid is a water-soluble B-group vitamin consisting of the residues of pteridine, p-aminobenzoic acid and glutamic acid, and is an essential substance for the growth and reproduction of body cells. It is present in liver, kidney, yeast and green vegetables such as beans, spinach, tomato, carrot, etc. and can be synthesized artificially. Folic acid is acted by dihydrofolate reductase and vitamin B12 to form tetrahydrofolic acid (THFA), which is combined with a plurality of one-carbon units (including CH3, CH2, CHO and the like) to form tetrahydrofolic acid coenzyme, transmits the one-carbon units, and participates in a plurality of important reactions in vivo and the synthesis of nucleic acid and amino acid. Under the action of serine transhydroxylase, THFA forms N-5, 10-methyl tetrahydrofolate, which can promote uracil nucleotide (dUMP) to form thymine nucleotide (dTMP), which can participate in DNA synthesis of cells and promote division and maturation of cells. During DNA synthesis, deoxyuridylic acid is converted to deoxythymidylate, during which the desired methyl group is provided by methylenetetrahydrofolate. When folic acid is deficient, DNA synthesis is slowed, but RNA synthesis is not affected, resulting in the formation of blood cells in the bone marrow with larger cell volume and more immature development of the nucleus, especially erythrocytes, which are most obvious and can have therapeutic effect when supplemented in time. Folic acid is absorbed in the proximal jejunum in a reduced form after oral administration, and appears in the blood 5-20 minutes, reaching a peak after one hour, with t1/2 of about 0.7 hour. The absorption rate of anemia patients is higher than that of normal people. Folic acid enters the liver from the portal vein, is stored in the liver in the form of N5-methyltetrahydrofolic acid and distributed to other tissues and organs, and the storage amount in the liver is about 1/3-1/2 of the total amount of the whole body. About 90% of the therapeutic amount of folic acid is excreted in urine, and 2 hours after bolus injection, 20% to 30% is present in urine.
Folic acid raw material medicines and tablets are collected in the second part of the China pharmacopoeia of the 2020 edition, wherein the tablets comprise two specifications of 0.4 mg/tablet and 5 mg/tablet. As a vitamin, 0.4 mg/tablet of small-size tablets are generally used for preventing congenital neural tube malformation of fetus and for preventing pregnant and lactating women in clinic, and are generally orally administered at a dose of 0.4mg once a day. The large-size tablet of 5 mg/tablet is generally used for folic acid deficiency caused by various reasons, megaloblastic anemia caused by folic acid deficiency and folic acid deficiency caused by chronic hemolytic anemia in clinic, and the dosage of 15-30 mg is generally orally taken by adults every day.
The difference between the drug amount of the 0.4 mg/tablet and the drug amount of the 5 mg/tablet is as much as 12.5 times, and especially for the 0.4 mg/tablet, the extremely low dosage of the drug has a plurality of difficulties in the preparation production, especially the problems of content uniformity and the like. For the huge difference of the drug amount between the specifications, folic acid tablets with two specifications need to be designed into two formulas with larger difference when being prepared, namely, one formula cannot be used for preparing the other tablet by means of equal scaling up or scaling down, for example, the size of the tablet is also limited, the weight of the ideal tablet is usually in the range of 70-300 mg, the tablet weight is difficult to manufacture when being too small, and the tablet weight is difficult to take when being too large, therefore, if the specification of 0.4mg is designed by the weight of 70mg, the tablet weight when the specification of 5mg is prepared by equal scaling up is 875mg, and the huge tablet is extremely difficult for a patient to take.
Therefore, those skilled in the art would expect to provide a method for preparing folic acid tablets with significant difference in drug content but insignificant difference in tablet weight, which would be expected to have excellent consistency of various physicochemical properties between different drug-containing specifications of folic acid tablets prepared by the method, or which would be expected to have good pharmaceutical properties such as excellent stability.
Disclosure of Invention
The invention aims to provide a method for preparing folic acid tablets with significant difference of drug content but insignificant difference of tablet weight, or the method aims to provide folic acid tablets with different drug-containing specifications and excellent consistency of various physicochemical properties, or the method aims to provide folic acid tablets with good pharmaceutical performance such as excellent stability. It has been surprisingly found that the present invention, based on the discovery that the process design of the recipe enables at least one of the above objects to be achieved.
To this end, the present invention provides in a first aspect a process for the preparation of folic acid tablets, comprising the steps of:
(1) fully mixing 0.4 weight part of folic acid with 1.5-2.5 weight parts, such as 2 weight parts, of fatty acid compound, then adding 4-6 weight parts, such as 5 weight parts, of cellulose, and uniformly mixing to obtain a preparation intermediate;
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) pressing the final mixed granules on a tablet press by using a punch die with a proper size to obtain the final product.
The method according to the first aspect of the present invention, wherein folic acid and various auxiliary materials are each previously pulverized into fine powders that can pass through 80 mesh.
The process according to the first aspect of the invention, wherein the fatty acid compound is a premix of fatty acid and calcium silicate, in particular a fatty acid and calcium silicate in a weight ratio of 2: 1.
The process according to the first aspect of the invention, wherein the fatty acid compound is selected from: stearic acid complex, palmitic acid complex, myristic acid complex, arachidic acid complex, the preferred fatty acid complex is stearic acid complex, especially the fatty acid complex is stearic acid and calcium silicate in a weight ratio of 2: 1. In one embodiment, the premix is prepared by passing a fine powder of stearic acid and a fine powder of calcium silicate, respectively, through 80 mesh screens in a weight ratio of 2: 1, and physically mixing the components in a ratio of 1.
The process according to the first aspect of the present invention, wherein the cellulose is microcrystalline cellulose.
The method according to the first aspect of the present invention, wherein the disintegrant is selected from the group consisting of corn starch, low-substituted hydroxypropyl cellulose.
The process according to the first aspect of the invention, wherein the disintegrant is used in an amount of 10 to 15% by weight of the total tablet weight, for example 12.5% by weight of the total tablet weight.
The method according to the first aspect of the present invention, wherein the amount of lactose is such that the compressed tablet has a weight per granule in the range of 70 to 250mg, especially a weight per granule in the range of 80 to 200mg, especially a weight per granule in the range of 80 to 150mg, especially a weight per granule in the range of 100 to 250mg, especially a weight per granule in the range of 120 to 250mg, especially a weight per granule in the range of 150 to 250 mg.
The process according to the first aspect of the invention, wherein the lactose is anhydrous lactose. As is well known, anhydrous lactose is generally used as direct compression lactose, which has excellent flowability and good compression performance and is widely used for direct compression of powder, and such lactose can be easily obtained directly from commercial sources as a product having a particle size of 80 mesh.
The method according to the first aspect of the invention, wherein the weight of folic acid in each tablet is 0.2-10 mg, such as 0.3-7.5 mg, such as 0.4-5 mg, such as 0.4mg, 0.1mg, 2mg, 5 mg.
By preparing the formulation intermediate and then mixing it with lactose in different amounts and tabletting according to the above preparation method and formulation, it was surprisingly found that the tablets obtained have a rather good consistency of physicochemical properties and, although a large correlation of the active ingredient content can be made, a small difference in tablet weight.
Further, the second aspect of the invention provides a folic acid tablet, which comprises the following components in parts by weight:
0.4 part by weight of folic acid,
1.5 to 2.5 parts by weight, for example, 2 parts by weight of a fatty acid compound,
4 to 6 parts by weight, for example 5 parts by weight, of cellulose,
the amount of disintegrant is 10-15% of the total weight of the tablet, for example 12.5% of the total weight of the tablet,
the amount of the lactose is such that the weight of each tablet is within 70-250 mg, especially within 80-200 mg, especially within 80-150 mg, especially within 100-250 mg, especially within 120-250 mg, especially within 150-250 mg.
The folic acid tablet according to the second aspect of the present invention has a weight of folic acid in each granule of 0.2 to 10mg, such as 0.3 to 7.5mg, such as 0.4 to 5mg, such as 0.4mg, 0.1mg, 2mg, 5 mg.
The folic acid tablet according to the second aspect of the present invention is prepared according to a method comprising the steps of:
(1) fully mixing 0.4 weight part of folic acid with 1.5-2.5 weight parts, such as 2 weight parts, of fatty acid compound, then adding 4-6 weight parts, such as 5 weight parts, of cellulose, and uniformly mixing to obtain a preparation intermediate;
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) pressing the final mixed granules on a tablet press by using a punch die with a proper size to obtain the final product.
The folic acid tablet according to the second aspect of the present invention, in which folic acid and various auxiliary materials are each previously pulverized into fine powder that can pass through 80 mesh, is provided.
The folic acid tablet according to the second aspect of the present invention, wherein the fatty acid compound is selected from the group consisting of: stearic acid complex, palmitic acid, myristic acid, arachidic acid, and the preferred fatty acid complex is stearic acid complex.
The folic acid tablet according to the second aspect of the present invention, wherein the cellulose is microcrystalline cellulose.
The folic acid tablet according to the second aspect of the present invention, wherein the disintegrant is selected from the group consisting of corn starch, low-substituted hydroxypropylcellulose.
Further, the third aspect of the present invention provides the use of a combination of the following materials in the manufacture of a medicament in the form of a tablet for the prevention of fetal congenital neural tube malformations, for prophylactic use in pregnant and lactating women, for folic acid deficiency caused by a variety of causes and megaloblastic anemia caused by folic acid deficiency, or for folic acid deficiency caused by chronic hemolytic anemia:
0.4 part by weight of folic acid,
1.5 to 2.5 parts by weight, for example, 2 parts by weight of a fatty acid compound,
4 to 6 parts by weight, for example 5 parts by weight, of cellulose,
the amount of disintegrant is 10-15% of the total weight of the tablet, for example 12.5% of the total weight of the tablet,
the amount of the lactose is such that the weight of each tablet is within 70-250 mg, especially within 80-200 mg, especially within 80-150 mg, especially within 100-250 mg, especially within 120-250 mg, especially within 150-250 mg.
The use according to the third aspect of the invention, wherein the weight of folic acid in each granule of the tablet is 0.2-10 mg, such as 0.3-7.5 mg, such as 0.4-5 mg, such as 0.4mg, 0.1mg, 2mg, 5 mg.
The use according to the third aspect of the present invention, wherein the tablet is prepared according to a process comprising the steps of:
(1) fully mixing 0.4 weight part of folic acid with 1.5-2.5 weight parts, such as 2 weight parts, of fatty acid compound, then adding 4-6 weight parts, such as 5 weight parts, of cellulose, and uniformly mixing to obtain a preparation intermediate;
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) pressing the final mixed granules on a tablet press by using a punch die with a proper size to obtain the final product.
According to the use of the third aspect of the present invention, folic acid and various excipients are each previously pulverized into fine powder that can pass through 80 mesh.
The use according to the third aspect of the invention, wherein the fatty acid compound is selected from: stearic acid complex, palmitic acid, myristic acid, arachidic acid, and the preferred fatty acid complex is stearic acid complex.
The use according to the third aspect of the invention, wherein the cellulose is microcrystalline cellulose.
The use according to the third aspect of the present invention, wherein the disintegrant is selected from the group consisting of corn starch, low substituted hydroxypropyl cellulose.
According to the method of the invention, a relatively wide active drug content in a relatively small tablet weight range can be achieved by preparing a preparation intermediate in advance, then mixing the preparation intermediate with a wide proportion of auxiliary materials and directly compressing into tablets.
The various embodiments of the various aspects of the invention may be combined with each other, as long as such combinations do not contradict each other.
The tablets, methods of preparation, pharmaceutical uses of the invention exhibit superior effects as described herein.
Detailed Description
The invention is further illustrated by the following specific examples. When tablets are prepared, the total amount of solid materials for tabletting of each batch of tablets is not less than 1kg, and the total material amount when the preparation intermediate is prepared for each batch is designed according to the test amount of the tablets. All expressed in mg by weight when describing the formulation. As not otherwise stated, folic acid and various adjuvants used in the examples of preparing tablets were all fine powders that could pass through 80 mesh. As not otherwise stated, the lactose used in the example of preparing tablets is commercially available anhydrous lactose, which can be used for direct compression of powders, with a commercial particle size of 80 mesh. When tablets are prepared in the following examples, the folic acid drug substance used is the same batch and complies with pharmacopoeia specifications, as not otherwise specified. In the following examples, tablets were prepared using stearic acid complex with stearic acid and calcium silicate in a weight ratio of 2: 1 by causing a stearic acid fine powder and a calcium silicate fine powder, which can pass through 80 mesh, respectively, to be mixed in a weight ratio of 2: 1, and physically mixing the components in a ratio of 1.
Example 1: preparation of folic acid tablets (each tablet containing folic acid 0.4mg)
1. Preparation of formulation intermediates
The formula is as follows: 0.4mg of folic acid, 2mg of stearic acid compound and 5mg of microcrystalline cellulose;
the preparation method comprises the following steps:
(1) fully mixing folic acid and stearic acid compound, adding microcrystalline cellulose, and uniformly mixing to obtain a preparation intermediate. Folic acid was contained at 0.4mg per 7.4mg of the formulation intermediate.
2. Preparation of tablets (each tablet containing folic acid 0.4mg)
Formulation 1 (amount per tablet): adding 7.4mg (containing folic acid 0.4mg), 10% (8mg) of total tablet weight of disintegrant (corn starch), and appropriate amount of lactose (64.6mg) to 80 mg;
formulation 2 (amount per tablet): 7.4mg of preparation intermediate (containing 0.4mg of folic acid), 12.5% of total tablet weight of disintegrant (corn starch) and proper amount of lactose added to 100mg of each tablet;
formulation 3 (amount per tablet): 7.4mg of preparation intermediate (containing 0.4mg of folic acid), 15% of total tablet weight of disintegrant (corn starch) and proper amount of lactose added to 150mg of each tablet;
formulation 4 (amount per tablet): 7.4mg of preparation intermediate (containing 0.4mg of folic acid), 10% of total tablet weight of disintegrant (low-substituted hydroxypropyl cellulose) and proper amount of lactose added to each tablet weight of 200 mg;
formulation 5 (amount per tablet): 7.4mg of preparation intermediate (containing 0.4mg of folic acid), 10% of total tablet weight of disintegrant (low-substituted hydroxypropyl cellulose) and proper amount of lactose added to 250mg of each tablet;
the preparation method comprises the following steps:
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) and (3) pressing the final mixed granules on a tablet machine by using a punch die with a proper size to form tablets (the hardness of the tablets is controlled within the range of 7-8 kg).
The mixing of the above-mentioned various materials can be easily carried out by various suitable apparatuses in the tablet manufacturing industry. The five tablets obtained in this example can be referred to as example 1 formulation 1, example 1 formulation 2, etc., respectively, with the remaining tablets being referred to by names in a similar manner.
Example 2: preparation of folic acid tablets (each tablet contains folic acid 2mg)
Using the preparation intermediate obtained in example 1 and the procedures of steps (2) to (3) of example 1, various tablets of this example were prepared.
Formulation 1 (amount per tablet): adding 37mg (containing folic acid 2mg), 10% (8mg) of total tablet weight of disintegrant (corn starch), and appropriate amount (35mg) of lactose to 80mg per tablet;
formulation 2 (amount per tablet): the preparation intermediate 37mg (containing folic acid 2mg), disintegrating agent (corn starch) 12.5% of the total tablet weight, and lactose in appropriate amount to 100mg per tablet;
formulation 3 (amount per tablet): the preparation intermediate 37mg (containing folic acid 2mg), 15% of total tablet weight of disintegrant (corn starch), and appropriate amount of lactose to 150mg per tablet;
formulation 4 (amount per tablet): adding preparation intermediate 37mg (containing folic acid 2mg), disintegrant (low-substituted hydroxypropyl cellulose) 10% of total tablet weight, and lactose in an amount of 200 mg;
formulation 5 (amount per tablet): the preparation intermediate 37mg (containing folic acid 2mg), disintegrant (low-substituted hydroxypropyl cellulose) 10% of total tablet weight, and lactose 250 mg.
Example 3: preparation of folic acid tablets (each tablet contains folic acid 5mg)
Using the preparation intermediate obtained in example 1 and the procedures of steps (2) to (3) of example 1, various tablets of this example were prepared.
Formulation 1 (amount per tablet): the preparation intermediate 92.5mg (containing folic acid 5mg), 10% (12mg) of total tablet weight of disintegrant (corn starch), and appropriate amount of lactose (15.5mg) added to 120mg per tablet;
formulation 2 (amount per tablet): 92.5mg (containing 5mg of folic acid) of the preparation intermediate, 12.5% of the total tablet weight of the disintegrant (corn starch) and a proper amount of lactose which is added to 150mg of each tablet weight;
formulation 3 (amount per tablet): 92.5mg (containing 5mg of folic acid) of the preparation intermediate, 10 percent of the total tablet weight of the disintegrant (low-substituted hydroxypropyl cellulose) and a proper amount of lactose which is added to 200mg of each tablet weight;
formulation 4 (amount per tablet): 92.5mg (containing 5mg of folic acid), 15% of total tablet weight of disintegrant (low-substituted hydroxypropyl cellulose), and appropriate amount of lactose added to each tablet weight of 250 mg.
Example 4: preparation of folic acid tablets
1. Preparation of formulation intermediates
The formula is as follows: 0.4mg of folic acid, 1.5mg of stearic acid compound and 6mg of microcrystalline cellulose;
the preparation method comprises the following steps: preparation intermediates were prepared according to step (1) of example 1, and each 7.9mg of preparation intermediates contained folic acid 0.4 mg.
2. Preparation of tablets
Formulation 1 (0.4 mg folic acid per tablet): 7.9mg of preparation intermediate (containing 0.4mg of folic acid), 15% of total tablet weight of disintegrant (low-substituted hydroxypropyl cellulose) and proper amount of lactose (added to 150mg of tablet weight);
formulation 2 (2 mg folic acid per tablet): the preparation intermediate 39.5mg (containing folic acid 2mg), 12.5% of total tablet weight of disintegrant (corn starch), and appropriate amount of lactose to 150mg per tablet;
formulation 3 (5 mg folic acid per tablet): 98.75mg of the preparation intermediate (containing 5mg of folic acid), 10% of the total tablet weight of the disintegrant (low-substituted hydroxypropyl cellulose) and a proper amount of lactose to 150mg of each tablet weight.
Each tablet of this example was prepared by the processes of steps (2) to (3) of example 1.
Example 5: preparation of folic acid tablets
1. Preparation of formulation intermediates
The formula is as follows: 0.4mg of folic acid, 2.5mg of stearic acid compound and 4mg of microcrystalline cellulose;
the preparation method comprises the following steps: preparation intermediates were prepared according to step (1) of example 1, and each 6.9mg of preparation intermediates contained folic acid 0.4 mg.
2. Preparation of tablets
Formulation 1 (0.4 mg folic acid per tablet): 6.9mg of preparation intermediate (containing 0.4mg of folic acid), 15% of total tablet weight of disintegrant (corn starch) and proper amount of lactose added to 150mg of each tablet;
formulation 2 (2 mg folic acid per tablet): preparation intermediate 34.5mg (containing folic acid 2mg), disintegrating agent (low substituted hydroxypropyl cellulose) 12.5% of total tablet weight, and lactose 150 mg;
formulation 3 (5 mg folic acid per tablet): the preparation intermediate 86.25mg (containing folic acid 5mg), 10% of total tablet weight of disintegrant (corn starch), and appropriate amount of lactose to 150mg per tablet weight.
Each tablet of this example was prepared by the processes of steps (2) to (3) of example 1.
Test example 1: content uniformity
The content uniformity of each folic acid tablet obtained in examples 1 to 5 was measured by referring to the method under the term "content uniformity" of folic acid tablets at page 233 of the second part of the "Chinese pharmacopoeia", 2020 edition, and the 2mg standard tablet was measured by the 0.4mg standard method. The calculated a +2.2S value should be equal to or less than L as specified for L = 15.0.
As a result: the a +2.2S values for all tablets of example 1 are between 3.36 and 5.28 such as a +2.2S =3.74 for the formula 1 tablet of example 1, the a +2.2S values for all tablets of example 2 are between 2.14 and 4.03 such as a +2.2S =3.36 for the formula 1 tablet of example 2, the a +2.2S values for all tablets of example 3 are between 3.51 and 5.16 such as a +2.2S =4.93 for the formula 1 tablet of example 3, the a +2.2S values for all tablets of example 4 are between 3.76 and 5.92 such as a +2.2S =4.64 for the formula 1 tablet of example 4, and the a +2.2S values for all tablets of example 5 are between 2.54 and 4.73 such as a +2.2S =3.31 for the formula 1 tablet of example 5.
From the above results, it can be seen that the content uniformity of each lot of tablets was quite excellent regardless of the large difference in active ingredient or the large difference in tablet weight.
Test example 2: dissolution rate
The determination is carried out according to the standard of the determination method of dissolution and release (the first method of 0931 in the general rules) of the four parts of the Chinese pharmacopoeia, 2020 edition, and according to the condition of the dissolution of the 233 folic acid tablets of the two parts of the Chinese pharmacopoeia, 2020 edition.
Dissolution conditions: taking 500ml of phosphate buffer solution (pH6.8) as a dissolution medium, rotating at 100 rpm, and sampling at 30min and 45min according to the method;
test solution: taking the dissolved liquid, filtering, and taking the subsequent filtrate;
control solution: taking a folic acid control product, precisely weighing, adding a dissolved medium for dissolving, and quantitatively diluting to prepare a solution containing about 10 mug, 5 mug, 1 mug and 0.5 mug in each 1 ml;
the determination is carried out by an HPLC method under the determination item of the folic acid content on page 232 of the second part of China pharmacopoeia of the 2020 edition.
As a result: the dissolution rate of 30min of the total tablet of example 1 is 76.1% + -1.2% (the + -1.2% is the relative standard deviation of the dissolution results of 5 tablets of example 1, the same applies hereinafter), the dissolution rate of 45min is 88.6% + -1.0%, the dissolution rates of two time points of the tablet of formula 1 of example 1 are 76.5% and 88.3% respectively, the dissolution rate of 30min of the total tablet of example 2 is 74.9% + -0.9%, the dissolution rate of 45min is 89.3% + -0.7%, the dissolution rates of two time points of the tablet of formula 1 of example 2 are 75.3% and 89.2% respectively, the dissolution rate of 30min of the total tablet of example 3 is 75.3% + -1.3%, the dissolution rate of 45min is 87.9% + -1.0%, the dissolution rates of two time points of the tablet of formula 1 of example 3 are 76.1% and 88.1% respectively, the dissolution rate of 30min of the dissolution rate of the tablet of the total tablet of example 4 is 76.3% + -1.0%, the dissolution rate of 45min is 90.1.0% and the dissolution rate of the tablet of formula 1.8% respectively, the dissolution rate of the whole tablet in example 5 is 75.2% + -1.1% at 30min, the dissolution rate of the tablet in 45min is 88.4% + -0.9%, and the dissolution rates of the tablet in example 5, formula 1 are 75.7% and 88.7% respectively at two time points. The dissolution rate of all the tablets in the above examples 1-5 is 75.6% + -1.7% in 30min, and the dissolution rate of 45min is 88.9% + -1.3%.
The tablets with the above dissolution rates were prepared in example 1 by adding lactose and the like in different amounts to 7.4mg of intermediate (0.4 mg of folic acid) to prepare tablets with weights of 80mg, 100mg, 150mg, 200mg and 250mg, in example 2 by adding lactose and the like in different amounts to 37mg of intermediate (2 mg of folic acid) to prepare tablets with weights of 80mg, 100mg, 150mg, 200mg and 250mg, in example 3 by adding lactose and the like in different amounts to 92.5mg of intermediate (5 mg of folic acid) to prepare tablets with weights of 120mg, 150mg, 200mg and 250mg, in example 4 and example 5, both tablets with weights of 150mg and folic acid of 0.4mg, 2mg and 5mg were prepared from the same intermediate in different amounts, which was designed similarly to the prescription of 150mg in examples 1 to 3.
From the dissolution rate results, no matter the active ingredients have great difference or the tablet weights have great difference, the dissolution rates of all batches of tablets are quite good, and the difference between different batches of tablets is extremely small; for example, in 5 tablets with equal dosage but large tablet weight difference in example 1, the relative standard deviation of the dissolution results at 30min is only 1.2%, and the relative standard deviation of the dissolution results at 45min is only 1.0%; for example, the deviation of dissolution rate results at 30min is only 1.0%, and the deviation of dissolution rate results at 45min is only 0.8% for the 3 tablets with the same weight but different dosages in example 4; the relative standard deviation of dissolution results at 30min was only 1.7% and at 45min was only 1.3% when all tablets were counted together. These results show that the preparation intermediate with a fixed formula ratio can be prepared in advance by the method of the invention, and then the preparation intermediate is mixed with auxiliary materials such as lactose and the like with different amounts to prepare tablets with different weights, or the preparation intermediate with very different differences is mixed with auxiliary materials such as lactose and the like to prepare tablets with smaller weight difference, and the dissolution rates of the tablets show quite consistent results. The inventors have found in additional experiments that mixing folic acid first with stearic acid complex is a prerequisite for obtaining the above mentioned dissolution properties, as can be seen in the following supplementary experiment a.
Supplementary test A: folic acid tablets were prepared and their dissolution was examined
Example 1 a: referring to the formulation and preparation of example 1, except that the stearic acid complex therein was replaced with stearic acid of equal weight (i.e., calcium silicate therein was partially replaced with stearic acid, i.e., 2mg of stearic acid complex was replaced with 2mg of stearic acid, which will be similarly referred to hereinafter as having the same meaning), 5 batches of tablets were prepared with increasing tablet weight, which were designated as E1a1, E1a2, E1a3, E1a4, E1a5, respectively; example 1 b: referring to the formulation and preparation of example 1, except that the stearic acid complex therein was replaced with equal weight of calcium silicate (i.e., stearic acid therein was partially replaced with calcium silicate, that is, 2mg of stearic acid complex was replaced with 2mg of calcium silicate, and the same meanings apply hereinafter to the similar expressions), 5 batches of tablets were prepared with increasing tablet weight, which were designated as E1b1, E1b2, E1b3, E1b4, and E1b5, respectively; example 1 c: referring to the formulation and preparation of example 1, except that the stearic acid complex therein was replaced with microcrystalline cellulose of equal weight, 5 batches of tablets were prepared, denoted by tablet weight E1c1, E1c2, E1c3, E1c4, E1c 5; example 2 a: referring to the formulation and preparation of example 2, except that the stearic acid complex was replaced with equal weight of stearic acid, 5 batches of tablets were made with increasing tablet weight, designated as E2a1, E2a2, E2a3, E2a4, E2a 5; example 2 b: referring to the formulation and preparation of example 2, 5 batches of tablets, designated E2b1, E2b2, E2b3, E2b4 and E2b5, were prepared with increasing tablet weight, except that the stearic acid complex therein was replaced with equal weight of calcium silicate; example 2 c: referring to the formulation and preparation of example 2, 5 batches of tablets, designated as E2c1, E2c2, E2c3, E2c4 and E2c5, were prepared with the exception that the stearic acid complex therein was replaced with microcrystalline cellulose of equal weight; example 3 a: referring to the formulation and preparation of example 3, except that the stearic acid complex was replaced with equal weight of stearic acid, 4 batches of tablets were made with increasing tablet weight, designated as E3a2, E3a3, E3a4, E3a 5; example 3 b: referring to the formulation and manufacturing process of example 3, 4 batches of tablets, designated as E3b2, E3b3, E3b4, E3b5, were prepared with equal weight of calcium silicate being replaced with the stearic acid complex therein; example 3 c: referring to the formulation and preparation of example 3, 4 batches of tablets were made, designated by E3c2, E3c3, E3c4, E3c5, respectively, with the exception that the stearic acid complex therein was replaced by an equal weight of microcrystalline cellulose. Next, the dissolution rates of the tablets obtained in examples 1a, 1b and 1c, the tablets obtained in examples 2a, 2b and 2c and the tablets obtained in examples 3a, 3b and 3c were measured by referring to the method of test example 2. As a result: example 1a total tablets having a dissolution rate of 78.1% + -6.7% at 30min, 89.4% + -5.3% at 45min, e.g. E1a1 tablets having a dissolution rate of 76.7% and 92.3% at two time points, respectively, example 1b total tablets having a dissolution rate of 76.7% + -6.4% at 30min, 45min dissolution rate of 91.2% + -5.1%, e.g. E1b1 tablets having a dissolution rate of 78.1% and 90.6% at two time points, example 1c total tablets having a dissolution rate of 79.6% + -7.3% at 30min, 45min dissolution rate of 87.6% + -5.8% at 45min, e.1 c1 tablets having a dissolution rate of 80.2% and 89.1% at two time points, respectively; example 2a total tablets having a dissolution rate of 74.5% + -6.5% at 30min, 92.1% + -5.7% at 45min, e.g. E2a1 tablets having a dissolution rate of 76.2% and 89.6% at two time points, example 2b total tablets having a dissolution rate of 79.4% + -7.2% at 30min, e.g. E2a1 tablets having a dissolution rate of 87.7% + -6.2% at 45min, e.g. E2b1 tablets having a dissolution rate of 80.4% and 90.1% at two time points, example 2c total tablets having a dissolution rate of 76.3% + -6.1% at 30min, a dissolution rate of 89.6% + -5.3% at 45min, e.2 c1 tablets having a dissolution rate of 75.4% and 87.9% at two time points, respectively; the dissolution rate of the whole tablet of example 3a at 30min is 77.6% + -6.7%, the dissolution rate of 45min is 91.1% + -5.6%, the dissolution rates of e.g. E3a 2% and 88.9% at two time points of the tablet are respectively 78.4% and 88.9%, the dissolution rate of the whole tablet of example 3b at 30min is 75.7% + -7.5%, the dissolution rate of 45min is 89.5% + -5.8%, the dissolution rates of e.g. E3b2 at two time points are respectively 73.8% and 91.4%, the dissolution rate of the whole tablet of example 3c at 30min is 78.4% + -6.2%, the dissolution rate of 45min is 87.8% + -6.0%, and the dissolution rate of e.3 c2 at two time points of the tablet are respectively 79.6% and 86.8%. All of the tablets obtained in examples 1a, 1b and 1c, examples 2a, 2b and 2c, and examples 3a, 3b and 3c above had a dissolution rate of 77.4% + -7.2% at 30min and a dissolution rate of 89.6% + -6.2% at 45 min.
Test example 3: determination of content
The contents of the tablets prepared in examples 1 to 5 were measured by referring to the method under the item "content measurement" of folic acid tablets at page 233 of the second part of the "Chinese pharmacopoeia", 2020 edition, wherein 2mg standard tablets were measured by referring to the method for measuring 5mg standard tablets, and the results were expressed as percentages of the labeled amounts. As a result: the indicated percentage of the total tablets of example 1 is 99.2 to 101.7% such as the 99.7% of the tablets of example 1 formulation 1, the indicated percentage of the total tablets of example 2 is 98.7 to 100.2% such as the 99.2% of the tablets of example 2 formulation 1, the indicated percentage of the total tablets of example 3 is 99.4 to 101.3% such as the 100.4% of the tablets of example 3 formulation 1, the indicated percentage of the total tablets of example 4 is 99.6 to 102.1% such as the 101.3% of the tablets of example 4 formulation 1, and the indicated percentage of the total tablets of example 5 is 99.0 to 100.6% such as the 99.4% of the tablets of example 5 formulation 1.
Test example 4: related substances
The quality of each tablet obtained in examples 1 to 5 was measured by referring to the method under the examination item of "related substances" in the second part 233 of the "Chinese pharmacopoeia" of 2020 edition. As a result:
folic acid raw material medicine: pteroic acid 0.248%, other individual impurities all <0.183%, each impurity except pteroic acid and <2.0% (1.164%); example 1 all tablets: pteroic acid is all <0.272%, other individual impurities are all <0.204%, each impurity other than pteroic acid and all <3.0% (<1.743%), for example 1 formulation 1 tablet: 0.258% of pteroic acid, less than 0.198% of other single impurities, and less than 3.0% (1.614%) of each impurity except pteroic acid; example 2 all tablets: pteroic acid is all <0.258%, other individual impurities are all <0.232%, each impurity other than pteroic acid and all <3.0% (<1.852%), for example 2 formulation 1 tablet: pteroic acid 0.251%, all other individual impurities <0.206%, each impurity other than pteroic acid and <3.0% (1.712%); example 3 all tablets: pteroic acid is all <0.284%, other individual impurities are all <0.217%, each impurity other than pteroic acid and all <3.0% (<1.931%), for example 3 formulation 1 tablet: pteroic acid 0.264%, all other individual impurities <0.195%, each impurity except pteroic acid and <3.0% (1.746%); example 4 all tablets: pteroic acid is all <0.278%, other individual impurities are all <0.228%, each impurity other than pteroic acid and all <3.0% (<1.814%), for example 4 formulation 1 tablet: pteroic acid 0.271%, all other individual impurities <0.213%, each impurity other than pteroic acid and <3.0% (1.687%); example 5 full tablets: pteroic acid is all <0.282%, other individual impurities are all <0.208%, each impurity other than pteroic acid and all <3.0% (<1.797%), for example 5 formulation 1 tablet: pteroic acid 0.271%, all other individual impurities <0.185%, each impurity except pteroic acid, and <3.0% (1.736%).
It is well known that pteroic acid in folic acid raw materials and formulations is a characteristic impurity and is a typical indicator of raw material and formulation stability. From the above results, the process of preparing folic acid into tablets of examples 1 to 5 does not cause significant increase of impurities, indicating that the preparation process is stable.
Test example 5: stability test
The tablets obtained in examples 1 to 5 were hermetically packed in a simulated marketed double aluminum blister, and then the tablets were placed in a 40 ℃ incubator for 6 months, and samples were taken at 0 month and 6 months, respectively, and the dissolution rate, content and related substances of the tablets were measured according to the methods of test examples 2 to 4. The data of test examples 2-4 are the 0 month results.
The dissolution result at 6 months has no obvious difference from the dissolution result at 0 month: example 1 total tablet 45min dissolution 88.4% ± 1.2% such as example 1 formulation 1 tablet dissolution 88.6%, example 2 total tablet 45min dissolution 89.1% ± 0.9% such as example 2 formulation 1 tablet dissolution 88.9%, example 3 total tablet 45min dissolution 88.2% ± 0.8% such as example 3 formulation 1 tablet dissolution 87.8%, example 4 total tablet 45min dissolution 89.8% ± 1.0% such as example 4 formulation 1 tablet dissolution 90.2%, example 5 total tablet 45min dissolution 88.6% ± 1.1% such as example 5 formulation 1 tablet dissolution 89.0%.
For each batch of tablets, the percentage of the content of the tablets divided by the content of the tablets in 0 month multiplied by 100% is the residual content after the treatment at 40 ℃ to 6 months, and the result is: example 1 total tablets have a residual 6 month content in the range of 97 to 99% such as 98.4% for example 1 formula 1 tablets, example 2 total tablets have a residual 6 month content in the range of 96 to 99% such as 97.3% for example 2 formula 1 tablets, example 3 total tablets have a residual 6 month content in the range of 97 to 100% such as 99.2% for example 3 formula 1 tablets, example 4 total tablets have a residual 6 month content in the range of 98 to 99% such as 98.7% for example 4 formula 1 tablets, and example 5 total tablets have a residual 6 month content in the range of 98 to 100% such as 99.1% for example 5 formula 1 tablets.
In the aspect of related substances, other single impurities, impurities except pteroic acid and two indexes of the tablet are basically not obviously changed after the tablet is treated at 40 ℃ to 6 months, the change is mainly reflected in the aspect of pteroic acid, and each batch of tablets are increased by a certain program; specifically, for each batch of tablets, the difference obtained by subtracting the content of 0 month from the content of 6 months is divided by the content of 0 months and then multiplied by 100 percent to obtain the pteroic acid increase rate after the treatment at 40 ℃ to 6 months, and the result is that: the 6-month pteroic acid increase rate of the whole tablet of example 1 is in the range of 37 to 46%, for example, 40.2% in the tablet of formula 1 of example 1, the 6-month pteroic acid increase rate of the whole tablet of example 2 is in the range of 28 to 39%, for example, 31.5% in the tablet of formula 1 of example 2, the 6-month pteroic acid increase rate of the whole tablet of example 3 is in the range of 34 to 45%, for example, 36.7% in the tablet of formula 1 of example 3, the 6-month pteroic acid increase rate of the whole tablet of example 4 is in the range of 39 to 44%, for example, 41.7% in the tablet of formula 1 of example 4, and the 6-month pteroic acid increase rate of the whole tablet of example 5 is in the range of 36 to 43%, for example, 39.4% in the tablet of formula 1 of example 5.
The stability test results show that the tablet of the invention has excellent chemical stability.
In addition, all the tablets obtained in the embodiments 1 to 5 of the invention are orange yellow tablets, which meet the property regulation under the item of the folic acid tablets at page 233 of the second part of the Chinese pharmacopoeia of the 2020 edition; according to a method for [ identification ] of folic acid tablets at 233 pages in the second part of the 'Chinese pharmacopoeia' of 2020 edition, all tablets obtained in examples 1 to 5 accord with the specification of the pharmacopoeia; when the dissolution rate of all 2mg and 5mg tablets obtained in examples 1 to 5 is determined by a method of '5 mg specification' under the dissolution rate item of a folic acid tablet at 233 p of the second part of the Chinese pharmacopoeia of 2020 edition, the dissolution rate at 45min is more than 70 percent and both meet the specification; all 0.4mg tablets obtained in examples 1 to 5 have a dissolution rate of more than 75% in 30min, which is determined by the method of 0.4mg standard under the dissolution rate of folic acid tablets 233 of the second part of the Chinese pharmacopoeia of 2020 edition, and all meet the regulations. These results show that various detection indexes of the tablet obtained by the invention completely accord with the pharmacopoeia regulations.
Generally speaking, the preparation intermediate can be prepared in the same proportion, the preparation intermediate can be directly compressed after being mixed with auxiliary materials such as lactose and the like in different proportions, tablets with different active medicament contents or tablets with the same active medicament content but larger difference in tablet weight can be obtained, and the unexpectedly found that the tablets with the large medicament content difference or the larger difference in tablet weight have excellent dissolution rate consistency, and the consistency is endowed by the combination of stearic acid and calcium silicate.
Although embodiments of the present disclosure have been described using specific terms, devices, and methods, such description is for illustrative purposes only. The words used are words of description rather than limitation. It is to be understood that variations and modifications may be effected by one of ordinary skill in the art without departing from the spirit and scope of the disclosure as set forth in the appended claims. Additionally, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. The spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.
Claims (10)
1. A folic acid tablet comprises the following components in parts by weight: 0.4 part of folic acid, 1.5-2.5 parts of fatty acid compound, 4-6 parts of cellulose, 10-15% of disintegrant and 80-250 mg of lactose.
2. The folic acid tablet according to claim 1, wherein the weight of folic acid in each granule is 0.2-10 mg.
3. The folic acid tablet of claim 1, prepared according to a method comprising the steps of:
(1) fully mixing 0.4 weight part of folic acid with 1.5-2.5 weight parts of fatty acid compound, then adding 4-6 weight parts of cellulose, and uniformly mixing to obtain a preparation intermediate;
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) pressing the final mixed granules on a tablet press by using a punch die with a proper size to obtain the final product.
4. The folic acid tablet according to claim 1, wherein folic acid and various auxiliary materials are each previously pulverized into fine powder passing through 80 mesh; alternatively, the fatty acid compound is a premix of a fatty acid and calcium silicate.
5. The folic acid tablet of claim 1, wherein the fatty acid compound is selected from the group consisting of: stearic acid complex, palmitic acid complex, myristic acid complex, arachidic acid complex.
6. The folic acid tablet of claim 1, wherein the cellulose is microcrystalline cellulose; alternatively, the fatty acid complex is a stearic acid complex.
7. The folic acid tablet according to claim 1, wherein the disintegrant is selected from the group consisting of corn starch, low-substituted hydroxypropylcellulose.
8. A process for the preparation of a folic acid tablet according to anyone of the claims 1 to 7, comprising the following steps:
(1) fully mixing 0.4 weight part of folic acid with 1.5-2.5 weight parts of fatty acid compound, then adding 4-6 weight parts of cellulose, and uniformly mixing to obtain a preparation intermediate;
(2) uniformly mixing the preparation intermediate obtained in the step (1), lactose and a disintegrating agent to obtain final mixed granules;
(3) pressing the final mixed granules on a tablet press by using a punch die with a proper size to obtain the final product.
9. The method of claim 8, wherein the fatty acid compound is a premix of fatty acid and calcium silicate.
10. Use of the folic acid tablet according to any one of claims 1 to 7 for the preparation of a medicament for the prevention of fetal congenital neural tube malformations, for prophylactic use in pregnant and lactating women, for folic acid deficiency caused by various causes and megaloblastic anemia caused by folic acid deficiency, or for folic acid deficiency caused by chronic hemolytic anemia.
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