CN114767645B - Folic acid tablet and preparation method thereof - Google Patents

Folic acid tablet and preparation method thereof Download PDF

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CN114767645B
CN114767645B CN202210452495.6A CN202210452495A CN114767645B CN 114767645 B CN114767645 B CN 114767645B CN 202210452495 A CN202210452495 A CN 202210452495A CN 114767645 B CN114767645 B CN 114767645B
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folic acid
mixture
tablet
microcrystalline cellulose
pregelatinized starch
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CN114767645A (en
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张蕾
蔡正军
李佳凯
肖学菊
杨卓理
韩雅慧
易斌
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Beijing Silian Pharmaceutical Industry Co ltd
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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
    • 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
    • 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
    • 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
    • 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
    • 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

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Abstract

The invention discloses a folic acid tablet which comprises the following raw material components in percentage by mass: 1-10% of folic acid; 8% -55% of microcrystalline cellulose; 8% -35% of pregelatinized starch; 0.1 to 1 percent of silicon dioxide; 0.5 to 1.5 percent of stearic acid and/or metal salt thereof; 15 to 65 percent of calcium hydrophosphate. The invention also discloses a preparation method of the folic acid tablet. Compared with the prior art, the invention has the following beneficial effects: according to the invention, through researching the prescription process of the folic acid tablet, the folic acid tablet can reach the target release requirement by matching with the silicon dioxide with a proper proportion and other auxiliary agents, the early release speed can be controlled, a good release platform can be achieved, and the final dissolution of folic acid is improved.

Description

Folic acid tablet and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a folic acid tablet and a preparation method thereof.
Background
Natural folic acid belongs to low molecular weight B-group water-soluble vitamins, named vitamin M, vitamin B9, R factors and the like, is also called pteroylglutamic acid, can not be synthesized and converted by human body, and almost participates in all methylation biochemical metabolic processes in vivo. It is present in many plant and animal tissues, mainly in the form of polyglutamate, and is only taken up by intestinal villus epithelial cells after hydrolysis to the monoglutamate by the glutamate carboxypeptidase enzyme encoded by the glutamate carboxypeptidase II gene. Folate deficiency can cause clinical diseases such as common folate deficiency megaloblastic anemia, neonatal nerve tube deformity, and more recently studied homocysteine. Because of insufficient intake of natural folic acid, a compound with a pteridine structure (N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino ] benzoyl ] -L-glutamic acid) is artificially synthesized in the last 50 th century, and is a precursor folic acid of natural folic acid (hereinafter referred to as folic acid, and the structure is shown as formula I).
Folic acid is absorbed in the upper jejunum after oral administration, and because of the presence of more polar groups in the Folic acid structure, it is absorbed slower and not completely, which presents a great challenge for the treatment of pre-increasing the dosage of Folic acid (MARTIN A.H, et al biodriver Monographs for Immediate Release Solid Oral Dosage Forms: folic acid,). J Pharm Sci.2017,); folic acid is converted into 5-methyltetrahydrofolate with physiological functions by sequentially passing through dihydrofolate reductase, tetrahydrofolate reductase and 5, 10-methylene folate reductase in small intestine epithelial cells and liver cells after oral absorption, and the folic acid which is not subjected to biological conversion enters a circulatory system and is rapidly discharged through kidneys.
In the prior art, high-density insoluble auxiliary materials are generally selected to slow down the dissolution rate of the product. Calcium hydrophosphate is a high-density indissoluble auxiliary material, the dosage of the calcium hydrophosphate is increased, the release is slowed down, and the final dissolution platform of the medicine is influenced. However, under the basket method condition specified in Chinese pharmacopoeia, calcium hydrophosphate falls down from basket holes too fast, is released too fast in the early stage, is not completely dissolved out by accumulation at the bottom of the later stage, and cannot meet the quality standard requirement of controlling release behavior. The dosage of calcium hydrophosphate is reduced, the fluidity of the material is poor, tabletting is affected, and the dissolution condition cannot be obviously improved. The dosage of the calcium hydrophosphate is increased, the early release behavior meets the requirement of the product quality standard, but the later bottom is seriously piled up, so that the final dissolution is lower, the near complete dissolution cannot be achieved, and the quality standard requirement is not met. The target quality cannot be achieved by adjusting the ratio. Thus, there is currently no highly desirable way to control the release behavior of folic acid tablets.
Disclosure of Invention
Based on the above, it is necessary to solve the above problems, and an object of the present invention is to provide a folic acid tablet and a preparation method thereof, which can control the early release rate of the calcium hydrophosphate and achieve a good release platform.
The invention can be realized by the following technical scheme:
in a first aspect of the present invention, a folic acid tablet is provided, comprising the following raw material components by mass percent:
1-10% of folic acid;
8% -55% of microcrystalline cellulose;
8% -35% of pregelatinized starch;
0.1 to 1 percent of silicon dioxide;
0.5 to 1.5 percent of stearic acid and/or metal salt thereof;
15% -65% of calcium hydrophosphate;
the silicon dioxide is selected from one or two of EVONIK R972 and EVONIK 200.
In one embodiment, the particle size of the raw material of the folic acid tablet is controlled to be 5 μm or less and D90. Ltoreq.10 μm.
In one embodiment, the metal salt of stearic acid is selected from magnesium stearate or sodium stearyl fumarate.
In one embodiment, the folic acid accounts for 4-6% by weight, the silicon dioxide accounts for 0.8-1% by weight, the calcium hydrophosphate accounts for 15-20% by weight, the microcrystalline cellulose accounts for 50-55% by weight, and the pregelatinized starch accounts for 22-28% by weight.
In one embodiment, the folic acid accounts for 1-2% by mass, the silicon dioxide accounts for 0.1-0.3% by mass, the calcium hydrophosphate accounts for 58-62% by mass, the microcrystalline cellulose accounts for 16-20% by mass, and the pregelatinized starch accounts for 18-22% by mass.
In a second aspect of the present invention, there is provided a method for preparing the folic acid tablet of the first aspect, the method comprising the steps of:
wet granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
In one embodiment, the wet granulation conditions include: the speed is 2 r/s-5 r/s, the cutter is 20 r/s-40 r/s, and the time is 4min-10 min.
In one embodiment, the method of preparation comprises the steps of:
dry granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
In one embodiment, the conditions for dry granulation include: the molding pressure is 65 bar-75 bar, the screw rotating speed is 30 rpm-50 rpm, the press roller rotating speed is 5 rpm-10 rpm, the grain screen is 1 mm-1.5 mm, and the finishing rotating speed is 150 rpm-200 rpm.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, through researching the prescription process of the folic acid tablet, the folic acid tablet can reach the target release requirement by matching with the silicon dioxide with a proper proportion and other auxiliary agents, the early release speed can be controlled, a good release platform can be achieved, and the final dissolution of folic acid is improved.
Drawings
FIG. 1 is a dissolution profile of an embodiment of the present invention;
FIG. 2 is a dissolution profile of a comparative example of the present invention.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
In the present invention, "first aspect", "second aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of the indicated technical features.
The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items. The terms "comprising," "including," and "comprising," as used herein, are synonymous, inclusive or open-ended, and do not exclude additional, unrecited members, elements, or method steps. In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
The percentage content referred to in the present invention refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.
The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.
CN113855641a discloses a preparation method of a solid preparation of folic acid, which is prepared by taking folic acid as an active ingredient and pharmaceutical excipients, wherein the pharmaceutical excipients comprise a stabilizer, an excipient and a lubricant; every 1000 tablets of folic acid solid preparation are composed of the following components in parts by weight: 0.4-5 g folic acid, 5-15 g stabilizer, 7090g excipient and 0.1-2.0 g lubricant; the stabilizer is selected from polyethylene glycol with one of molecular weight ranges 3350, 4000 or 6000; the excipient is selected from two or more of microcrystalline cellulose, corn starch, pregelatinized starch, lactose, sucrose, dextrin, mannitol, xylitol and calcium hydrophosphate; the lubricant is one or more of talcum powder, silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate and is prepared by the following method: step one: pulverizing folic acid, and sieving with 200 mesh sieve; step two: granulating the folic acid after the crushing treatment, excipient and stabilizer; step three: drying the prepared particles at 40-70 ℃; step four: finishing the dried granules by using a 20-30-mesh screen; step five: adding lubricant into the particles and mixing for 5-10 minutes; step six: tabletting, wherein the hardness of the tablets is controlled to be 2-6 kg; or directly encapsulating the granules. The conventional formulation requires the addition of stabilizers to maintain stability.
In a first aspect, an embodiment of the present invention provides a folic acid tablet, which includes the following raw material components by mass percent:
1-10% of folic acid;
8% -55% of microcrystalline cellulose;
8% -35% of pregelatinized starch;
0.1 to 1 percent of silicon dioxide;
0.5 to 1.5 percent of stearic acid and/or metal salt thereof;
15 to 65 percent of calcium hydrophosphate.
According to the invention, through researching the prescription process of the folic acid tablet, compared with common silicon dioxide, the silicon dioxide with a proper proportion is matched with other auxiliary agents, so that the folic acid tablet can reach the target release requirement, the early release speed can be controlled, a good release platform can be achieved, and the final dissolution of folic acid is improved. In addition, the folic acid tablet provided by the invention is combined with proper auxiliary materials in a scientific proportion by screening, so that the obtained total mixed particles have good fluidity, the tabletting requirement is met, the influence of temperature and humidity on the raw material medicines is reduced, and the generation of relevant substances in the folic acid preparation process is reduced. In particular, compared with the traditional technology, the folic acid tablet formula provided by the invention can obtain a stabilizing effect under the condition of avoiding adding a stabilizing agent.
In the present invention, unless otherwise indicated, all numbers expressing quantities of ingredients, physical and chemical properties, and so forth used in the specification and claims are to be understood as being about the same in all instances except as indicated in the operating examples or where otherwise indicated. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached claims are approximations that can be varied appropriately by those skilled in the art utilizing the desired properties sought to be obtained by the teachings disclosed herein. The use of numerical ranges by endpoints includes all numbers subsumed within that range as well as any range within that range, e.g., 1% to 10% includes 1%, 1.1%, 1.3%, 1.5%, 2%, 2.75%, 3%, 3.80%, … … 9.9.9%, 10%, and the like.
The folic acid products of the present invention are suitable for use in tablets. The tablet is a tablet or special-shaped tablet solid preparation which is prepared by uniformly mixing and pressing the medicines and auxiliary materials, and mainly comprises an oral common tablet, a buccal tablet, a sublingual tablet, an oral patch and the like. The tablets may be coated for stability, to mask unpleasant odors of the drug, to improve the appearance of the tablet, etc.
The folic acid in the folic acid tablet of the present invention may be 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1% by mass 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10%.
Silica is produced by hydrolysis of volatile chlorosilanes in oxyhydrogen flame. From a chemical point of view, these loose white powders consist of amorphous silica of high purity. The silica is wettable with water and dispersible in water.
Preferably, the mass ratio of the calcium bicarbonate, the microcrystalline cellulose and the silicon dioxide is (50-65): (8-24): (0.1-0.3).
Preferably, the silica of the embodiments of the present invention is selected from the group consisting of EVONIK200 (specific surface area 175m 2 /g～225m 2 /g) and EVONIKR972 (90 m) 2 /g～130m 2 /g) type silica. The invention discovers that the used EVONIK 200/R972 type silicon dioxide has good lubrication effect and can obviously improve the material fluidity; after the silica of the type is used, the drug release can be obviously slowed down by 5-10 percent; through observing the disintegration phenomenon, the use of the silicon dioxide can effectively prevent the calcium hydrophosphateAnd folic acid is slowly and stably released when the rotating basket falls in the rotating basket hole, and finally the platform period meeting the requirements is reached.
The mass percentage of silica in the folic acid tablet of the present invention may be 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%.
The microcrystalline cellulose (MCC) of the invention is mainly composed of linear polysaccharide substances combined by beta-1, 4-glucosidic bond, and is white, odorless and tasteless crystalline powder which is formed by hydrolyzing natural cellulose to extremely fine short rod-shaped or powdery porous particles with limited degree of polymerization (LODP) through dilute acid and can flow freely.
Optionally, the microcrystalline cellulose is selected from PH12, PH101, PH102 or PH105, has good compressibility, has the functions of adhesion, glidant, disintegration and the like, and is suitable for the tabletting process of folic acid tablets of the component. The pressed tablet has good hardness and is easy to disintegrate.
The mass percentage of microcrystalline cellulose in the folic acid tablet of the present invention may be 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%.
The mass percentage of pregelatinized starch in the folic acid tablet of the present invention may be 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%.
In some embodiments, the metal salt of stearic acid is selected from magnesium stearate or sodium stearyl fumarate.
The mass percentage of stearic acid and/or metal salts thereof in the folic acid tablet of the present invention may be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%.
Optionally, the calcium hydrogen phosphate is selected from one or two of anhydrous calcium hydrogen phosphate and dihydrate calcium hydrogen phosphate.
The mass percentage of the calcium hydrogen phosphate in the folic acid tablet of the present invention may be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%.
Preferably, the folic acid accounts for 4-6% by weight, the silicon dioxide accounts for 0.8-1% by weight, the calcium hydrophosphate accounts for 15-20% by weight, the microcrystalline cellulose accounts for 50-55% by weight, and the pregelatinized starch accounts for 22-28% by weight.
Preferably, the mass percentage of folic acid is 1% -2%, the mass percentage of silicon dioxide is 0.1% -0.3%, the mass percentage of calcium hydrophosphate is 58% -62%, the mass percentage of microcrystalline cellulose is 16% -20%, and the mass percentage of pregelatinized starch is 18% -22%.
The words "preferably", "more preferably" in the context of the present invention refer to embodiments of the invention which may in some cases provide certain benefits. However, other embodiments may be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
Preferably, the folic acid tablet does not contain lactose. Although lactose is a common excipient in pharmaceutical formulations, especially in tablets, the inventors have found that the use of lactose in folic acid tablets containing silica does not improve the dissolution of folic acid tablets, but rather results in too fast a premature dissolution rate of folic acid tablets and incomplete total dissolution.
In a second aspect, an embodiment of the present invention further provides a method for preparing the folic acid tablet according to the first aspect, including the following steps:
mixing the raw material components, tabletting and preparing folic acid tablets.
In some embodiments, the method of making comprises the steps of:
wet granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
In some embodiments, the wet granulation conditions include: the speed is 2 r/s-5 r/s, the cutter is 20 r/s-40 r/s, and the time is 4min-10 min.
In some embodiments, the preparation method is as follows:
(1) Micronizing folic acid raw material medicine, and controlling the granularity D90 of the raw material medicine to be less than or equal to 5 μm and less than or equal to 10 μm.
(2) Weighing calcium hydrophosphate, microcrystalline cellulose (MCC), pregelatinized starch, stearic acid or/and metal salt thereof and silicon dioxide according to the prescription amount;
(3) The crushed folic acid raw material medicine is weighed after being dried and purified according to COA;
(4) Mixing: dispersing microcrystalline cellulose and folic acid, adding into a wet granulator, adding calcium hydrophosphate and pregelatinized starch, stirring for 2 r/s-5 r/s (preferably 4 r/s), and cutting for 20 r/s-40 r/s (preferably 30 r/s) for 4min-10min (preferably 4 min) to obtain a first mixture;
(5) Total mixing: mixing the first mixed powder, magnesium stearate and silicon dioxide by adopting a mixer, and mixing for 5min to obtain a second mixture;
(6) Tabletting: tabletting by using a phi 6 flat inclined punch, wherein the hardness is 3 kg-6 kg, and the tablet weight is 100mg;
(7) And (3) inner packaging: PVC is used for aluminum-plastic packaging.
In some embodiments, the preparation method comprises the steps of:
dry granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
In some embodiments, the conditions of dry granulation include: the molding pressure is 65 bar-75 bar, the screw rotating speed is 30 rpm-50 rpm, the press roller rotating speed is 5 rpm-10 rpm, the grain screen is 1 mm-1.5 mm, and the finishing rotating speed is 150 rpm-200 rpm.
In some embodiments, the folic acid tablets are prepared by a dry granulation method, and the preparation method is as follows:
(1) Micronizing folic acid raw material medicine, controlling the granularity D90 of the raw material medicine to be more than or equal to 5 μm and less than or equal to 10 μm;
(2) Weighing calcium hydrophosphate, microcrystalline cellulose (MCC), pregelatinized starch, magnesium stearate and silicon dioxide according to the prescription amount;
(3) The crushed folic acid raw material medicine is weighed after being dried and purified according to COA;
(4) Mixing: dispersing microcrystalline cellulose and folic acid, adding into a three-dimensional mixer, and then adding calcium hydrophosphate and pregelatinized starch, wherein the rotating speed is 13rpm, and the time is 8-15 min (optimally 10 min);
(5) Dry granulating the mixed powder by an LGS120 dry granulator, forming the mixed powder at a pressure of 70bar, wherein the rotating speed of a feeding screw rod is 30-50 rpm (optimal 40 rpm), the rotating speed of a pressing roller is 5-10 rpm (optimal 8 rpm), the rotating speed of a granulating screen is 1.2mm, the rotating speed of the granulating screen is 150-200 rpm (optimal 180 rpm), preparing intermediate particles, and controlling the fine powder rate (65-mesh screen) to be not more than 40%, thus obtaining first mixed powder particles;
(6) Total mixing: mixing the first powder mixing particles, magnesium stearate and silicon dioxide by adopting a mixer, and mixing for 5min;
(7) Tabletting: tabletting by using a phi 6 flat inclined punch, wherein the hardness is 3 kg-6 kg, and the tablet weight is 100mg;
(8) And (3) inner packaging: PVC is used for aluminum-plastic packaging.
The temperature of the production process in the present invention is not particularly limited, and it is allowed to be either constant temperature treatment or treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The folic acid tablet and the preparation method thereof according to the present invention are described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
TABLE 1
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 65
Microcrystalline cellulose PH101 8.4
Pregelatinized starch Luo Gaite 20
Silica dioxide EVONIK200 0.1
Stearyl sodium fumarate The state of lake 1.5
Example 2
TABLE 2
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 50
Microcrystalline cellulose PH102 23.2
Pregelatinized starch Luo Gaite 20
Silica dioxide EVONIK 200 0.3
Magnesium stearate Liaoning aoda 1.5
Example 3
TABLE 3 Table 3
Example 4
TABLE 4 Table 4
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Anhydrous type 15
Microcrystalline cellulose PH102 53.5
Pregelatinized starch Luo Gaite 25
Silica dioxide EVONIK R972 1
Magnesium stearate Liaoning aoda 0.5
Example 5
TABLE 5
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 1
Dibasic calcium phosphate Dihydrate of 59.5
Microcrystalline cellulose PH105 18.4
Pregelatinized starch Luo Gaite 20
Silica dioxide EVONIK 200 0.1
Stearic acid The state of lake 1
Example 6
TABLE 6
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 10
Dibasic calcium phosphate Anhydrous type 40
Microcrystalline cellulose PH12 13.7
Pregelatinized starch Luo Gaite 35
Silica dioxide EVONIK 200 0.8
Magnesium stearate Liaoning aoda 0.5
Comparative example 1
TABLE 7
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 65
Microcrystalline cellulose PH101 8.4
Pregelatinized starch Luo Gaite 20
Silica dioxide The state of lake 0.1
Stearyl sodium fumarate The state of lake 1.5
Comparative example 2
TABLE 8
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 50
Microcrystalline cellulose PH102 23.5
Pregelatinized starch Luo Gaite 20
Magnesium stearate Liaoning aoda 1.5
Comparative example 3
TABLE 9
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 50
Microcrystalline cellulose PH102 24.5
Pregelatinized starch Luo Gaite 18
Silica dioxide EVONIK 200 2
Magnesium stearate Liaoning aoda 0.5
Comparative example 4
Table 10
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 50
Microcrystalline cellulose PH102 23.2
Pregelatinized starch Luo Gaite 20
Talc powder Dragon-Sheng Huamei 0.3
Magnesium stearate Liaoning aoda 1.5
Comparative example 5
TABLE 11
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 33.5
Microcrystalline cellulose PH102 40
Pregelatinized starch Luo Gaite 20
Silica dioxide The state of lake 1
Magnesium stearate Liaoning aoda 0.5
Comparative example 6
Table 12
Composition of the components Manufacturer/model Content%
Folic acid Hebei Ji Heng 5
Dibasic calcium phosphate Dihydrate of 50
Microcrystalline cellulose PH102 23.2
Pregelatinized starch Luo Gaite 20
Silica dioxide The state of lake 0.3
Stearic acid Liaoning aoda 1.5
The EVONIK200 silica in the above examples and comparative examples had a specific surface area of 175m 2 /g～225m 2 Silica/g, EVONIK type R972 silica having a specific surface area of 90m 2 /g～130m 2 Silica/g.
The content is the final concentration of the components in the folic acid tablet in percentage by mass.
Examples 1 to 5 and comparative examples 1 to 6 were prepared by a powder direct compression method as follows:
(1) Micronizing folic acid raw material medicine, and controlling the granularity D90 of the raw material medicine to be less than or equal to 5 μm and less than or equal to 10 μm.
(2) Calcium hydrogen phosphate, microcrystalline cellulose (MCC), pregelatinized starch, magnesium stearate and silicon dioxide are weighed according to the prescribed amounts.
(3) And (5) weighing the crushed folic acid raw material medicine after being dried and purified according to COA.
(4) Mixing: dispersing microcrystalline cellulose and folic acid, adding into wet granulator, adding calcium hydrogen phosphate and pregelatinized starch, stirring for 4r/s, and cutting for 30r/s for 4min.
(5) Total mixing: mixing the above powder, magnesium stearate and silicon dioxide with a mixer, and mixing at 13Hz for 5min.
(6) Tabletting: tabletting by using a phi 6 flat inclined punch, wherein the hardness is 3-6 kg, and the tablet weight is 100mg.
(7) And (3) inner packaging: PVC is used for aluminum-plastic packaging.
Example 6 was prepared using a dry granulation process as follows:
(1) Micronizing folic acid raw material medicine, and controlling the granularity D90 of the raw material medicine to be less than or equal to 5 μm and less than or equal to 10 μm.
(2) Calcium hydrogen phosphate, microcrystalline cellulose (MCC), pregelatinized starch, magnesium stearate and silicon dioxide are weighed according to the prescribed amounts.
(3) And (5) weighing the crushed folic acid raw material medicine after being dried and purified according to COA.
(4) Mixing: dispersing microcrystalline cellulose and folic acid, adding into a three-dimensional mixer, and adding calcium hydrogen phosphate and pregelatinized starch at 13rpm for 10min.
(5) Dry granulating the mixed powder by an LGS120 dry granulator, wherein the forming pressure is 70bar, the rotating speed of a feeding screw rod is 30-50 rpm (optimal 40 rpm), the rotating speed of a pressing roller is 8rpm, the granulating screen is 1.2mm, the granulating rotating speed is 180rpm, intermediate granules are prepared, and the fine powder rate (65-mesh screen) is controlled to be not more than 40%.
(6) Total mixing: mixing the above granules, magnesium stearate and silicon dioxide with a mixer, 13Hz, and mixing for 5min.
(7) Tabletting: tabletting by using a phi 6 flat inclined punch, wherein the hardness is 3-6 kg, and the tablet weight is 100mg.
(8) And (3) inner packaging: PVC is used for aluminum-plastic packaging.
Test one:
reference formulation: folic acid tablet, trade name: specafoldine manufacturer: MERUS LABS LUXCO s. 5mg, lot number: 20FA445.
The detection method comprises the following steps:
taking reference preparation, example and comparative example samples, and completing the following operations according to four dissolution and release measurement methods (general rule 0931 first method) of Chinese pharmacopoeia 2020 edition:
TABLE 13
The in vitro dissolution results are shown in table 14, table 15, fig. 1 and fig. 2 below.
TABLE 14 comparison of in vitro dissolution Curve results
Time/min Reference formulation Example 1 Example 2 Example 3 Example 4 Example 5 Example 6
0 0 0 0 0 0 0 0
5 35 29 32 26 30 26 29
10 48 43 46 41 44 42 43
15 55 53 54 52 55 53 54
30 69 71 68 71 75 69 74
45 79 81 78 84 86 80 86
60 85 88 83 91 94 85 91
90 91 94 93 98 99 93 95
TABLE 15 comparison of in vitro dissolution Curve results
From the above results, it can be seen that:
examples 1 to 6 self-made samples were fitted with reference formulations by using silica (preferably EVONIK200, EVONIK R972 type) in combination with dibasic calcium phosphate (anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate) to control the dissolution rate.
Compared with example 1, comparative examples 1 and 5 use ordinary silica, and the sample dissolution rate is faster and slower than that before and after the reference preparation, and the accumulation is serious, so that the ideal platform is not achieved. The amount of calcium hydrogen phosphate in comparative example 1 was more than that in comparative example 5, and the dissolution end point was lower due to the accumulation effect.
Compared with example 2, comparative example 6 uses ordinary silica, and the sample dissolution rate is faster and slower than that before and after the reference preparation, and the accumulation is serious, so that the ideal platform is not reached, and the sample is accumulated at the bottom of the dissolution cup, so that the release degree is not ideal.
In comparison with example 2, comparative example 2 was prepared without silica, and the dissolution appearance was observed as if the insoluble auxiliary material rapidly dropped in the spin basket and accumulated at the bottom of the dissolution cup, resulting in unsatisfactory release.
The formulation of comparative example 3, which has an excessively large proportion of silica and too slow dissolution overall, does not fit the reference formulation, and demonstrates that silica (preferably types EVONIK200, EVONIK R972) has an effect of controlling the dissolution rate, as compared to examples 1, 2.
In comparison with example 3, in the formulation of comparative example 4, talc was used as a lubricant, and it was found from the test results that talc could not replace silica and had the effect of controlling elution.
The above results illustrate: the silicon dioxide can control the falling speed of the high-density insoluble auxiliary material calcium hydrophosphate under the condition of a basket method in the prescription of the invention, and control the dissolution and release rate of the phylloic acid so as to achieve the target quality of the product. In particular EVONIK 200/R972 silica appears prominent. The proportion of silica is also very important for the dissolution effect and the preparation process of the formulation is preferably a powder direct compression process.
In the embodiment of the invention, the EVONIK200 and EVONIK R972 colloidal silica has excellent physicochemical properties, and can rapidly wrap materials with poor fluidity due to the larger specific surface area, thereby playing a role in flow assistance.
In the research and development process of the folic acid tablet, after EVONIK200 and EVONIK R972 are used in the formula, folic acid raw materials are wrapped by colloidal silica with larger specific surface area, so that the fluidity is improved, the dissolution rate is reduced, and a self-made sample dissolution curve can be fitted with a reference preparation.
The inventors examined the repose angles of the mixed powders before tabletting of example 1 and comparative example 1, and the results are shown in the following Table 16:
table 16
Sample of Height (cm) Radius of bottom surface (cm) Tangent value Angle of repose
Example 1 2.7 4.25 0.64 32.7°
Comparative example 1 4.4 4.25 1.04 46.2°
From the above measurement results, it was found that the raw material formulation of the EVONIK200 silica used in example 1 had better flowability than the raw material formulation of the conventional silica used in comparative example 1.
Test two, stability (6 months stability acceleration):
and (3) placing the prepared sample under acceleration conditions (40 ℃ +/-2 ℃, 75%RH+/-5%RH), taking out the sample after 1, 2, 3 and 6 months, detecting related substances, and inspecting the stability of the sample. According to the inspection method of relevant substances under folic acid tablet item in the current Chinese pharmacopoeia, the relevant substances of each example, comparative example and reference preparation sample are detected, and the results are as follows:
TABLE 17
The test result of the stability test of the acceleration test shows that the results of 6 months under the acceleration condition of the prescription of each embodiment meet the Chinese pharmacopoeia standard, and the maximum single impurity (impurity A) can be controlled within the limit of 1.0 percent.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. The scope of the invention is, therefore, indicated by the appended claims, and the description may be intended to interpret the contents of the claims.

Claims (9)

1. The folic acid tablet is characterized by comprising the following raw material components in percentage by mass:
1-10% of folic acid;
8% -55% of microcrystalline cellulose;
8% -35% of pregelatinized starch;
0.1 to 1 percent of silicon dioxide;
0.5 to 1.5 percent of stearic acid and/or metal salt thereof;
15% -65% of calcium hydrophosphate;
the silicon dioxide is selected from one or two of EVONIK R972 and EVONIK 200;
the metal salt of stearic acid is selected from magnesium stearate or sodium stearyl fumarate.
2. The folic acid tablet of claim 1, wherein the particle size of the raw material of the folic acid tablet is controlled to be 5 μm-d90-10 μm.
3. Folic acid tablet according to any of the claims 1 to 2, characterised in that it comprises, by mass, 4% to 6% folic acid, 0.8% to 1% silicon dioxide, 15% to 20% dibasic calcium phosphate, 50% to 55% microcrystalline cellulose and 22% to 28% pregelatinized starch.
4. Folic acid tablet according to any of the claims 1 to 2, characterised in that it comprises, by mass, 1% to 2% folic acid, 0.1% to 0.3% silicon dioxide, 58% to 62% dibasic calcium phosphate, 16% to 20% microcrystalline cellulose and 18% to 22% pregelatinized starch.
5. The method for producing a folic acid tablet according to any one of claims 1 to 4, comprising the steps of:
mixing the raw material components, tabletting and preparing folic acid tablets.
6. The method of preparing folic acid tablets of claim 5, comprising the steps of:
wet granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
7. The method of preparing folic acid tablets of claim 6, wherein the wet granulation conditions include: the speed is 2 r/s-5 r/s, the cutter is 20 r/s-40 r/s, and the time is 4min-10 min.
8. The method of preparing folic acid tablets of claim 5, comprising the steps of:
dry granulating the microcrystalline cellulose, folic acid, calcium hydrophosphate and pregelatinized starch to prepare a first mixture;
mixing said stearic acid or/and a metal salt thereof, silica and said first mixture to produce a second mixture;
tabletting the second mixture to prepare folic acid tablets.
9. The method of preparing folic acid tablets of claim 8, wherein the dry granulation conditions include: the molding pressure is 65 bar-75 bar, the screw rotating speed is 30 rpm-50 rpm, the press roller rotating speed is 5 rpm-10 rpm, the grain screen is 1 mm-1.5 mm, and the finishing rotating speed is 150 rpm-200 rpm.
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