CN112156096A - Folic acid sustained-release composition, sustained-release preparation and application thereof - Google Patents
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Abstract
The invention relates to the field of medicines, in particular to a folic acid sustained-release composition, a folic acid sustained-release preparation and application thereof. The invention provides a folic acid sustained-release preparation, which adopts a gastric retention technology and can prolong the retention time of folic acid preparation in stomach to more than 6 hours. Compared with a common release preparation, the sustained-release preparation has less administration frequency, and is reduced to once a day from 2-3 times a day, unexpectedly, the preparation has a faster 5-methyltetrahydrofolate level lifting rate compared with the common folic acid common release preparation, and the dosage of the 5-methyltetrahydrofolate reaching the same organism can be reduced by about 50% compared with the dosage of the common release preparation on a rat animal model. The sustained-release preparation can be used for patients who need to take folic acid for a long time, such as folic acid-deficient megaloblastic anemia; hyperhomocysteinemia with folate deficiency; and stroke prevention and myocardial infarction caused by homocysteine; folic acid deficiency induced depression and anxiety disorders.
Description
Technical Field
The invention relates to the field of medicines, in particular to a folic acid sustained-release composition, a folic acid sustained-release preparation and application thereof.
Background
Natural folic acid belongs to the group B water-soluble vitamins of low molecular weight, which has been found to be named: vitamin M and vitamin B9R factor, also known as pteroylglutamic acid, is unable to be synthesized and transformed by human body and almost participates in all biochemical metabolic processes of methylation in vivo. It is present in many plant and animal tissues, mainly in the form of polyglutamate, and is hydrolyzed to monoglutamate by glutamate carboxypeptidase encoded by glutamate carboxypeptidase II gene, and can be absorbed by small intestinal villus epithelial cells. In the last 50 th century, compounds with pteridine-like structure (N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino had been artificially synthesized due to insufficient intake of natural folic acid]Benzoyl radical]-L-glutamic acid) is dHowever, folic acid, a precursor of folic acid (hereinafter abbreviated as folic acid, with a structure shown in formula I), folic acid deficiency can cause various clinical diseases, such as common folic acid deficiency megaloblastic anemia, neonatal neural tube malformation, and homocysteine which is researched more in recent years.
Folic acid is absorbed in the upper part of the jejunum after Oral administration, and is absorbed more slowly and incompletely due to the presence of more polar groups in the folate structure, which presents a great challenge to therapies that are intended to increase the dose of administered Folic acid (MARTIN A.H, et al, biogauver monograms for Immediate Release Oral Dosage Forms: Folic acid, J Pharm Sci.2017); after the folic acid is orally absorbed, the folic acid is converted into the physiological 5-methyl tetrahydrofolic acid by the dihydrofolate reductase, the tetrahydrofolate reductase and the 5, 10-methylene folate reductase in small intestinal epithelial cells and liver cells in sequence, and the folic acid which is not biologically converted enters a circulatory system and is rapidly discharged by the kidney. Because of the gene polymorphism of the folate convertase, the biotransformation of the enzyme has the characteristic of easy saturation, which results in poor biotransformation capability of part of patients, and when a large dose of drug administration is clinically needed, a large amount of unconverted folic acid enters the circulatory system and is discharged through the kidney. On the one hand, the renal excretion of a large amount of Folic Acid increases the renal burden, which causes the damage of renal function, especially for patients with the defect of renal function, and the renal excretion of a large amount of unconverted Folic Acid also causes the obvious shortage of 5-methyltetrahydrofolic Acid with physiological function in vivo, which may be one of the reasons that some patients have no effect in the clinical extensive use of Folic Acid for preventing the neural Tube malformation of newborn in recent 20 years (Apolline I et al. neural Tube Defects, Folic Acid and methylation. int J.environ.2013,10:4352-4389), especially the modern medical research shows that the family with high incidence rate of neural Tube malformation of newborn, patients with hyperhomocysteine, patients with stroke, patients with myocardial infarction and the like are all related to the metabolic activity of Folic Acid with low enzyme. Clinically, the intake of folic acid is generally expected to be increased, but the clinical effect is not ideal.
Disclosure of Invention
In view of the above, the invention provides a folic acid sustained-release composition, a sustained-release preparation and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a folic acid slow-release composition which comprises the following components in parts by weight:
0.75 to 6.67 parts by weight of folic acid
60-92 parts by weight of slow release material
3-30 parts of a bleaching agent;
the slow release material comprises one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carbomer and chitosan;
the bleaching agent comprises one or a mixture of more than two of carbonate, high polymer material, hexadecanol, octadecanol, stearic acid and glyceryl monostearate.
In some embodiments of the invention, the carbonate comprises one or a mixture of two or more of sodium bicarbonate, sodium carbonate, magnesium carbonate, calcium carbonate; the polymer material comprises crospovidone.
In some embodiments of the present invention, the composition comprises the following components in parts by weight:
folic acid 3.33 weight portions
Sustained release material 85.17 weight portions
10 parts of bleaching agent.
Based on the research, the invention also provides the application of the folic acid slow-release composition in preparing folic acid slow-release preparations.
The invention also provides a folic acid sustained-release preparation which comprises the folic acid sustained-release composition and pharmaceutically acceptable auxiliary materials.
In some embodiments of the invention, the excipient comprises one or a mixture of two of talc, aerosil and magnesium stearate.
In some embodiments of the present invention, the composition comprises the following components in parts by weight:
in some embodiments of the present invention, the composition comprises the following components in parts by weight:
in some embodiments of the present invention, the dosage form comprises one or more of a folic acid sustained-release matrix tablet, a folic acid sustained-release pellet, a folic acid sustained-release capsule or a folic acid sustained-release micro-tablet;
in some embodiments, the method for preparing the folic acid sustained-release matrix tablet comprises the following steps: mixing folic acid with the slow release material, the bleaching agent and the anti-sticking agent, and tabletting by a direct powder tabletting process or adding a binding agent for wet granulation to prepare the folic acid slow release matrix tablet; the greater the viscosity of the polymeric material, the slower the drug release. The variety and amount of the bleaching agent affect the bleaching time of the preparation in the stomach. The invention controls the release of the medicament for more than 6 hours by controlling the viscosity of the high polymer material and the variety and the quantity of the bleaching agent, thereby achieving the slow release effect.
Specifically, the preparation method of the folic acid sustained-release matrix tablet comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m (optimally 10 mu m), and weighing the raw and auxiliary materials;
(2) sequentially adding folic acid, HPMC K1500 and sodium bicarbonate into a high-speed stirring and mixing granulator, stirring at 100-200 rpm (optimally 120rpm), cutting at 1000-2200 rpm (optimally 1400rpm) for 4-10 min (optimally 5 min);
(3) transferring the mixed materials into a three-dimensional mixer, adding magnesium stearate according to the prescription amount, and rotating at a speed: 13rpm for 4-10 min (optimally 5 min);
(4) tabletting: by shallow recesses
The hardness of the punched piece is controlled to be 2.5-5.0 kg (preferably 4.0 kg).
In some embodiments, the preparation method of the folic acid sustained-release pellet comprises the following steps: mixing folic acid with the sustained-release material, adding wetting agent to make soft mass, making into pellet, and drying; making into folic acid sustained release pellet.
In some embodiments, the preparation method of the folic acid sustained-release pellet comprises the following steps: mixing folic acid with the sustained-release material and the bleaching agent, mixing with the wetting agent, preparing soft material, preparing pellet, and drying to obtain folic acid sustained-release pellet.
In some embodiments, the folic acid sustained-release capsule is prepared by a method comprising: mixing folic acid with the sustained release material and the bleaching agent, mixing with the wetting agent, preparing soft material, preparing pellet, drying to obtain folic acid sustained release pellet, and encapsulating to obtain folic acid sustained release pellet capsule.
In some embodiments, the folic acid sustained-release capsule is prepared by a method comprising: mixing folic acid with polymer material, adding wetting agent such as water or ethanol water solution, making soft mass, extruding with extrusion spheronizer, spheronizing to obtain pellet, and drying the pellet; coating a layer of polymer material with a bleaching agent on the dry pellets in a nonporous coating machine by a powder coating method. And filling the folic acid sustained-release pellets with different drug release speeds into a capsule to obtain the folic acid sustained-release pellet capsule with floating sustained-release function. Or adding folic acid into polymer material and bleaching agent, mixing, adding appropriate amount of wetting agent such as water or ethanol water solution to obtain soft material, extruding and rounding by an extrusion and rounding machine to obtain pellet, drying the pellet to obtain folic acid sustained-release pellet with gastric floating effect, and encapsulating the pellets with different drug release speeds to obtain folic acid sustained-release pellet capsule.
Specifically, the preparation method of the folic acid sustained-release capsule comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m (optimally 10 mu m), and weighing the raw and auxiliary materials according to the formula.
(2) The folic acid, the HPMC K200M, the HPMC K100 and the calcium carbonate are sequentially added into a wet mixing granulator, and are stirred at 100-200 rpm (optimally 130rpm), a cutter at 1000-2200 rpm (optimally 1500rpm) is used for 4-10 min (optimally 5 min).
(3) Adding a proper amount of water, stirring at 150-250 rpm (preferably 180rpmn), and cutting at 1800-2800 rpm (preferably 2000rpm) to obtain a soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 0.8mm, and the extrusion speed is as follows: extruding the strips at 30-60 rpm (optimally 40rpm), and controlling the adding amount of the adhesive so as to control the length of the extruded strips.
(5) The extruded strip-shaped objects are moved into a spheronizer, the extruded objects are cut off at the rotating speed of 50-140 Hz (best 100Hz), and then spheronization is carried out for 10-20 min (best 15min) at the rotating speed of 30-100 Hz (best 50Hz), so as to prepare the micro-pills with the diameter of about 1.0 mm.
(6) And (3) drying: and (4) transferring the mixture into a drying room for drying, wherein the drying temperature is 40-50 ℃ (optimally 50 ℃), and respectively sieving the mixture by using a 14-mesh sieve and a 20-mesh sieve.
(7) Filling: the capsule shell No. 3 is adopted for filling, and the filling amount is 100 mg.
In some embodiments, the folic acid sustained-release micro-tablets are prepared by a method comprising: mixing folic acid with the sustained release material, the bleaching agent and magnesium stearate, and tabletting to obtain the final product.
In some embodiments, the folic acid sustained-release micro-tablet capsule is prepared by a method comprising the following steps: adding high molecular material, bleaching agent and magnesium stearate into folic acid, preparing micro tablets with diameter less than 4mm by a micro tablet press, and filling the micro tablets into capsules to obtain folic acid sustained release capsules.
Specifically, the preparation method of the folic acid sustained-release micro-tablet capsule comprises the following steps: (1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m (optimally 10 mu m), and weighing the raw and auxiliary materials according to the formula.
(2) The folic acid, the HPMC K100M and the sodium bicarbonate are sequentially added into a V-shaped stirring mixer, and stirred at 40-100 rpm (optimally 80rpm) for 10-30 min (optimally 20 min).
(3) Transferring the mixed materials into a three-dimensional mixer, adding magnesium stearate according to the prescription amount, and rotating at a speed: 13rpm, and 4-10 min (preferably 5 min).
(4) Tabletting: and (3) pressing 4.0mm micro tablets by using a micro tablet press, wherein the hardness is controlled to be 2.0-5.0 kg (optimally 3.0 kg).
(5) Filling: and 3# capsule shells are adopted for filling.
The invention also provides the folic acid slow-release composition or the folic acid slow-release preparation for preparing a medicine for preventing and/or treating megaloblastic anemia, newborn neural tube malformation, other diseases caused by folic acid deficiency or folic acid relative insufficiency; the other diseases comprise one or more of hyperhomocysteinemia, cerebral apoplexy and cognitive dysfunction.
Since the folic acid absorption part is positioned at the front end of the jejunum, an obvious absorption window exists, and the common membrane-controlled and skeleton-type folic acid sustained-release preparations obviously cannot achieve the aim of the invention. The invention provides a folic acid sustained-release preparation with high biotransformation, which can be retained in the stomach for a long time, the preparation can control folic acid to be slowly released in the stomach for a long time, the folic acid after being released is absorbed by the front ends of duodenum and jejunum, and is more efficiently converted into 5-methyltetrahydrofolic acid with biological function by corresponding enzyme in the process of passing through small intestinal epithelial cells and liver cells. The method has important significance for improving the biological curative effect of folic acid and reducing the side effect of the kidney.
The beneficial effects of the invention include but are not limited to:
(1) folic acid is a drug with a certain absorption window, and is mainly absorbed at the front end of the small intestine, and the drug with the absorption window is not suitable for being designed into a sustained-release preparation according to the design concept of the sustained-release preparation, but the sustained-release preparation has gastric retention capacity, so that the sustained-release purpose is achieved. The sustained release preparation of folic acid provided by the invention mainly comprises a folic acid release retarder and a retarder for preventing the preparation from being rapidly transported from stomach to intestine, wherein the retarder is mainly a polymer material with proper viscosity, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carbomer, chitosan and the like; and some can swell in the stomach when meeting liquid, reduce the density of preparation itself, can make the preparation unit float in the stomach for a short time, it is called as floating agent for short, this kind of supplementary product mainly includes carbonate such as sodium bicarbonate, sodium carbonate, magnesium carbonate, calcium carbonate, etc., and have high-molecular material of the void fraction, such as high-molecular material such as cross-linked polyvidone of the high void fraction, supplementary product such as cetyl alcohol, octadecanol, stearic acid, glycerin monostearate of lower density characteristic; for well-known reasons, other excipients which are generally required for the formulation, such as talc for anti-adhesive action, aerosil, magnesium stearate for lubricating action, etc. The sustained-release preparation of folic acid can be in the forms of folic acid skeleton tablets, folic acid skeleton pellets, reloading capsules or micro-tablets, reloading capsules and the like from appearance.
(2) The key point of the invention is that the unexpected effect is achieved, the bioavailability of the sustained-release preparation is generally lower than or equal to that of the normal-release preparation, but the bioavailability of the sustained-release preparation is higher than that of the normal-release preparation by taking 5-methyltetrahydrofolic acid as an investigation index, and the bioavailability of the sustained-release preparation is improved by about 1 time in a folic acid metabolic disorder model mouse.
(3) The folic acid sustained-release preparation can replace the existing folic acid to treat clinical indications clinically, such as the treatment of megaloblastic anemia and the prevention of neural tube malformation of newborn, and can also be used for treating other diseases caused by folic acid deficiency or relative folic acid deficiency, such as hyperhomocysteinemia, cerebral apoplexy, cognitive dysfunction and the like. And the existing folic acid dosage form is mainly characterized in that the folic acid sustained-release preparation uses lower dosage than the current common dosage. Compared with the conventional release preparation, the folic acid sustained-release preparation has the same clinical application, the same 5-methyltetrahydrofolic acid level is improved, the folic acid sustained-release preparation has lower dosage or higher improving speed, and the renal function burden of renal excretion increase of a large amount of folic acid can be avoided. Compared with a common-release preparation of folic acid, the medicine is also taken less frequently, and the probability of missing the medicine taken by a patient can be reduced.
Detailed Description
The invention discloses a folic acid sustained-release composition, a sustained-release preparation and application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The synthesized folic acid can be converted into 5-methyltetrahydrofolic acid in vivo and participate in biochemical metabolism of various methylation in vivo, and the specifications of the synthesized folic acid on the market at present comprise 0.4mg folic acid tablets and 5mg folic acid tablets. 0.4mg folic acid is mainly used for the neural tube malformation of newborn and the folic acid supplement of pregnant women in pregnancy, and one tablet is generally taken one day; the 5mg standard is mainly used for megaloblastic anemia caused by folic acid deficiency, the usage is 5 mg/time and 3 times/day, and as the megaloblastic anemia has a long treatment period which is generally more than 4 months, and the phenomenon of drug missing is caused by multiple times of daily administration, the sustained-release preparation which can be administered once a day has obvious advantages in the aspects of reducing drug missing and improving patient compliance, so the invention is invented based on the application defects of the existing market products. Meanwhile, folic acid is absorbed in vivo by oral administration and has an absorption window phenomenon, so common sustained-release technical means, such as a membrane-controlled sustained-release technology and a skeleton-type sustained-release technology are difficult to meet the requirement of folic acid sustained release, and the folic acid sustained-release preparation of the gastric retention technology can keep the folic acid preparation retained in the stomach for a long time so as to achieve the purpose of full absorption of the folic acid.
The composition of the present invention is composed of folic acid, a retarder of folic acid release and a retention agent for rapid gastric transit to the small intestine, a foaming agent for assisting the retention of the retarder in the stomach, and a lubricant required for general formulations for known reasons.
The folic acid release retarder and the retarder for preventing the preparation from being rapidly transported from the stomach to the intestine are mainly polymer materials with proper viscosity, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carbomer, chitosan and the like; and some can swell in the stomach when meeting liquid, reduce the density of preparation itself, make the preparation unit float in the stomach briefly, it is called floating agent for short, this kind of supplementary product mainly includes carbonate such as sodium bicarbonate, sodium carbonate, magnesium carbonate, calcium carbonate, etc., and have high-molecular material of the high void fraction, such as high-molecular material such as cross-linked polyvidone of the high void fraction, supplementary product such as cetyl alcohol, octadecanol, stearic acid, glycerin monostearate, etc. of the lower density characteristic; for well-known reasons, other excipients which are generally required for the formulation, such as talc for anti-adhesive action, aerosil, magnesium stearate for lubricating action, etc.
TABLE 1
The folic acid sustained release preparation can be realized by a matrix tablet, a matrix pellet, a micro-tablet or the like.
Different sustained-release preparation forms of folic acid have different preparation methods:
a matrix tablet of folic acid sustained release preparation. The folic acid is taken, evenly mixed with the high polymer material, the bleaching agent and the anti-sticking agent, and then the folic acid sustained-release matrix tablet is prepared by a direct powder tabletting process or wet granulation by adding an adhesive and then tabletting. The greater the viscosity of the polymeric material, the slower the drug release. The variety and amount of the bleaching agent affect the bleaching time of the preparation in the stomach. The invention controls the release of the medicament for more than 6 hours by controlling the viscosity of the high polymer material and the variety and the quantity of the bleaching agent, thereby achieving the slow release effect.
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 μm (preferably 10 μm), and weighing the raw materials and auxiliary materials.
(2) The folic acid, the HPMC K1500 and the sodium bicarbonate are sequentially added into a high-speed stirring and mixing granulator, the stirring is carried out at 100-200 rpm (optimally 120rpm), the cutter is carried out at 1000-2200 rpm (optimally 1400rpm), and the time is 4-10 min (optimally 5 min).
(3) Transferring the mixed materials into a three-dimensional mixer, adding magnesium stearate according to the prescription amount, and rotating at a speed: 13rpm, and 4-10 min (preferably 5 min).
(4) Tabletting: by shallow recesses
The hardness of the punched piece is controlled to be 2.5-5.0 kg (preferably 4.0 kg).
Folic acid sustained-release matrix pellets. Mixing folic acid with polymer material, adding wetting agent such as water or ethanol water solution, making soft mass, extruding with extrusion spheronizer, spheronizing to obtain pellet, and drying the pellet; coating a layer of polymer material with a bleaching agent on the dry pellets in a nonporous coating machine by a powder coating method. And filling the folic acid sustained-release pellets with different drug release speeds into a capsule to obtain the folic acid sustained-release pellet capsule with floating sustained-release function. Or adding folic acid into polymer material and bleaching agent, mixing, adding appropriate amount of wetting agent such as water or ethanol water solution to obtain soft material, extruding and rounding by an extrusion and rounding machine to obtain pellet, drying the pellet to obtain folic acid sustained-release pellet with gastric floating effect, and encapsulating the pellets with different drug release speeds to obtain folic acid sustained-release pellet capsule.
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m (optimally 10 mu m), and weighing the raw and auxiliary materials according to the formula.
(2) The folic acid, the HPMC K200M, the HPMC K100 and the calcium carbonate are sequentially added into a wet mixing granulator, and are stirred at 100-200 rpm (optimally 130rpm), a cutter at 1000-2200 rpm (optimally 1500rpm) is used for 4-10 min (optimally 5 min).
(3) Adding a proper amount of water, stirring at 150-250 rpm (preferably 180rpm), and cutting at 1800-2800 rpm (preferably 2000rpm) to obtain a soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 0.8mm, and the extrusion speed is as follows: extruding the strips at 30-60 rpm (optimally 40rpm), and controlling the adding amount of the adhesive so as to control the length of the extruded strips.
(5) The extruded strip-shaped objects are moved into a spheronizer, the extruded objects are cut off at the rotating speed of 50-140 Hz (best 100Hz), and then spheronization is carried out for 10-20 min (best 15min) at the rotating speed of 30-100 Hz (best 50Hz), so as to prepare the micro-pills with the diameter of about 1.0 mm.
(6) And (3) drying: and (4) transferring the mixture into a drying room for drying, wherein the drying temperature is 40-50 ℃ (optimally 50 ℃), and respectively sieving the mixture by using a 14-mesh sieve and a 20-mesh sieve.
(7) Filling: the capsule shell No. 3 is adopted for filling, and the filling amount is 100 mg.
Micro-tablets of folic acid sustained release preparation. Adding high molecular material, bleaching agent and magnesium stearate into folic acid, preparing micro tablets with diameter less than 4.0mm by a micro tablet press, and filling the micro tablets into capsules to obtain folic acid sustained release capsules.
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m (optimally 10 mu m), and weighing the raw and auxiliary materials according to the formula.
(2) The folic acid, the HPMC K100M and the sodium bicarbonate are sequentially added into a V-shaped stirring mixer, and stirred at 40-100 rpm (optimally 80rpm) for 10-30 min (optimally 20 min).
(3) Transferring the mixed materials into a three-dimensional mixer, adding magnesium stearate according to the prescription amount, and rotating at a speed: 13rpm, and 4-10 min (preferably 5 min).
(4) Tabletting: and (3) pressing 4.0mm micro tablets by using a micro tablet press, wherein the hardness is controlled to be 2.0-5.0 kg (optimally 3.0 kg).
(5) Filling: and 3# capsule shells are adopted for filling.
The invention provides a folic acid sustained-release preparation, which has less administration frequency than a normal-release preparation, and is reduced to once a day from 2-3 times a day, unexpectedly, the folic acid sustained-release preparation has a faster 5-methyltetrahydrofolate level lifting rate than the normal-release folic acid preparation, and the drug dosage of the folic acid sustained-release folic acid can be reduced by about 50% compared with the normal-release folic acid sustained-release folic acid in a rat animal model when reaching the same organism 5-methyltetrahydrofolate level.
Since folic acid is mainly absorbed at the front end of the jejunum, it has a distinct absorption window. According to the design scheme of the conventional sustained release preparation, the optimal absorption window of the medicament is missed, for example, the common membrane-controlled and gel sustained release preparation has the medicament release time of more than 6 hours, and the time for folic acid to pass through the optimal absorption window is generally not more than 3 hours. The sustained release preparation adopts a gastric retention technology, and can prolong the retention time of the folic acid preparation in the stomach to more than 6 hours.
The folic acid sustained-release preparation is a pellet or a sustained-release preparation of micro-tablets by utilizing the group drug release characteristics, so that the potential safety hazard caused by the tiny defects of the design of common sustained-release preparations, such as sustained-release tablets, can be avoided.
The sustained-release preparation can be used for patients who need to take folic acid for a long time, such as folic acid-deficient megaloblastic anemia; hyperhomocysteinemia with folate deficiency; and stroke prevention and myocardial infarction caused by homocysteine; folic acid deficiency induced depression and anxiety disorders.
In the folic acid sustained-release composition, the sustained-release preparation and the application thereof provided by the invention, the used raw materials and the preparation can be purchased from the market.
The invention is further illustrated by the following examples:
example 1:
10g of folic acid, 30g of HPMC K1500255.5g, 4.5g of sodium bicarbonate and 4.5g of magnesium stearate are uniformly mixed, the hardness is controlled to be 2.5-5.0 kg, and the mixture is pressed into folic acid tablets with the weight of 150mg, so that 5mg of folic acid is contained in each tablet. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 2.
TABLE 2
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) The folic acid, HPMC K1500 and sodium bicarbonate are sequentially added into a high-speed stirring and mixing granulator, the stirring speed is 120rpm, the cutter speed is 1000rpm, and the time is 5 min.
(3) Adding magnesium stearate into a three-dimensional mixer, rotating at the speed: 13rpm for 4 min.
(4) Tabletting: by shallow recesses
The hardness of the punched piece is controlled to be 2.5-5.0 kg.
Example 2:
taking 20g of folic acid, 245.5g of hydroxypropyl cellulose (HPC), 30g of sodium bicarbonate and 4.5g of magnesium stearate, uniformly mixing, controlling the hardness to be 2.5-5.0 kg, and pressing into folic acid tablets with the weight of 150mg to obtain folic acid containing 10mg of folic acid in each tablet. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 3.
TABLE 3
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) Folic acid, hydroxypropyl cellulose (HPC) and sodium bicarbonate were added sequentially to a V-blender mixer and stirred at 50rpm for 10 min.
(3) Adding magnesium stearate into a three-dimensional mixer, rotating at the speed: 13rpm for 4 min.
(4) By shallow recesses
The hardness of the punched piece is controlled to be 2.5-5.0 kg.
Example 3:
taking 10g of folic acid, HPMC K750194 g and 90g of calcium carbonate, uniformly mixing, adding a proper amount of water to prepare a soft material, adding the soft material into a WL350 extrusion rounding machine, controlling the size of a sieve mesh and rounding conditions to obtain micro-pills with the diameter of about 2mm, drying at 40-50 ℃, respectively sieving with a 10-mesh sieve and a 14-mesh sieve to obtain micro-pills with the size of 1.4-2 mm and the slow-release effect, adding magnesium stearate, filling 150mg of micro-pills per capsule, and filling capsules to obtain the micro-pills with the folic acid content of 5mg per capsule. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 4.
TABLE 4
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) The folic acid, HPMC K750 and calcium carbonate are sequentially added into a wet mixing granulator, the stirring speed is 120rpm, the cutting knife is 1500rpm, and the time is 5 min.
(3) Adding a proper amount of water, stirring at 180rpm, and cutting at 2000rpm to obtain a soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 1.5mm, and the extrusion speed is as follows: 40rpm, the strands were extruded and the amount of adhesive added was controlled to control the length of the extruded strands.
(5) The extruded strands were transferred to a spheronizer, which cut the extrudate at 80Hz and spheronize at 40Hz for 15min to produce pellets with a diameter of about 2.0 mm.
(6) Transferring into a drying room for drying at 50 deg.C, and sieving with 10 mesh sieve and 14 mesh sieve respectively.
(7) Adding magnesium stearate, mixing, and filling with No. 3 capsule shell to obtain 150 mg.
Example 4:
taking 4g of folic acid, 100g of HPMC K100M 270 and 20g of calcium carbonate, uniformly mixing, adding a proper amount of water, preparing a soft material, adding into a WL350 extrusion spheronizer, controlling the size of a sieve pore and the spheronization condition to obtain a pellet with the diameter of about 1.5mm, drying at 40-50 ℃, respectively sieving with a 12-mesh sieve and a 18-mesh sieve to obtain a pellet with the sustained release effect and the size of 1.0-1.7 mm, and adding magnesium stearate and silicon dioxide. Filling 150mg of micro-pills into each capsule to obtain 2mg of folic acid contained in each capsule. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 5.
TABLE 5
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) The folic acid, HPMC K100M and calcium carbonate are sequentially added into a wet mixing granulator, and stirred at 130rpm/min, and the cutter at 1400rpm/min lasts for 5 min.
(3) Adding a proper amount of water, stirring at 160rpm, cutting at 1800rpm, and making soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 1.0mm, and the extrusion speed is as follows: 40rpm, the strands were extruded and the amount of adhesive added was controlled to control the length of the extruded strands.
(5) Transferring the extruded strip into a spheronizer, cutting the extrudate at 90Hz, and spheronizing at 50Hz for 15min to obtain pellets with diameter of about 1.5 mm.
(6) Transferring into a drying room for drying at 50 deg.C, and sieving with 12 mesh sieve and 18 mesh sieve respectively.
(7) Adding silicon dioxide and magnesium stearate, mixing, and filling with No. 3 capsule shell to obtain 150 mg.
Example 5:
the folic acid sustained-release preparation pellets obtained in example 3 and example 4 were mixed according to the ratio of 1: 1(w/w) ratio, total weight 150mg filled capsules. The dissolution rate and the time to float were measured by keeping out of light with 900ml of 0.1mol/LHCl medium.
The preparation method comprises the following steps:
(1) mixing: the folic acid sustained release preparation pellets prepared in example 3 and example 4 were prepared according to the following ratio of 1: adding 1(w/w) of the mixture into a three-dimensional mixer for mixing, wherein the rotating speed is as follows: 13rpm, and 4-10 min (preferably 5 min).
(2) Filling: the capsule shell No. 3 is adopted for filling, and the filling amount is 150 mg.
Example 6:
taking 4g of folic acid, 200 g of HPMC K200M 736, 100g of HPMC K100100 g and 150g of calcium carbonate, uniformly mixing, adding a proper amount of water, softening, adding into a WL350 extrusion spheronization machine, controlling the size of a sieve pore and the spheronization condition to obtain micro-pills with the diameter of about 1.0mm, drying at 40-50 ℃, respectively sieving with a 14-mesh sieve and a 20-mesh sieve to obtain micro-pills with the size of 0.84-1.4 mm and having a slow release effect, and adding magnesium stearate. Filling 100mg pellets in each capsule, obtaining 0.4mg folic acid in each capsule, using 0.1mol/LHCl medium 900ml to avoid light, measuring the dissolution rate and the floating time, and the results are shown in Table 6.
TABLE 6
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) The folic acid, HPMC K200M, HPMC K100 and calcium carbonate are sequentially added into a wet mixing granulator, and the mixture is stirred at 130rpm and cut at 1400rpm for 5 min.
(3) Adding a proper amount of water, stirring at 180rpm, and cutting at 2000rpm to obtain a soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 0.8mm, and the extrusion speed is as follows: 40rpm, the strands were extruded and the amount of adhesive added was controlled to control the length of the extruded strands.
(5) The extruded strands were transferred to a spheronizer, which cut the extrudate at 100Hz and spheronized at 50Hz for 15min to produce pellets with a diameter of about 1.0 mm.
(6) Transferring into a drying room for drying at 50 deg.C, and sieving with 14 mesh sieve and 20 mesh sieve respectively. .
(7) Adding magnesium stearate, mixing, and filling with No. 3 capsule shell to obtain 100 mg.
Example 7:
taking 10g of folic acid, 35 g of HPMC K35M 525g, 1500300 g of HPMC K and 150g of calcium carbonate, uniformly mixing, adding a proper amount of water, softening, adding into a WL350 extrusion spheronizer, controlling the size of a sieve pore and the spheronization condition to obtain micro-pills with the diameter of about 1.2mm, drying at 40-50 ℃, respectively sieving by a 14-mesh sieve and a 20-mesh sieve to obtain micro-pills with the size of 0.84-1.4 mm and the slow release effect, filling capsules according to 100mg of the micro-pills in each capsule to obtain the micro-pills with the folic acid content of 1.0mg in each capsule, keeping out of the sun by 0.1mol/LHCl medium 900ml, measuring the dissolution rate, and measuring the bleaching time, wherein the results are shown in Table 7.
TABLE 7
The preparation method comprises the following steps:
(1) micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Weighing the raw materials and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 20 mu m.
(2) Sequentially adding folic acid, HPMC K35M, HPMC K1500, and calcium carbonate into wet mixing granulator, stirring at 120rpm, cutting at 1500rpm, and standing for 5 min.
(3) Adding a proper amount of water, stirring at 180rpm, and cutting at 2000rpm to obtain a soft material.
(4) Adding the prepared soft material into a WL350 extrusion rounding machine, wherein the diameter of a sieve pore is 1.2mm, and the extrusion speed is as follows: 40rpm, the strands were extruded and the amount of adhesive added was controlled to control the length of the extruded strands.
(5) The extruded strands were transferred to a spheronizer, which cut the extrudate at 100Hz and spheronized at 50Hz for 15min to produce pellets with a diameter of about 1.2 mm.
(6) Transferring into a drying room for drying at 50 deg.C, and sieving with 14 mesh sieve and 20 mesh sieve respectively.
(7) Adding magnesium stearate, mixing, and filling with No. 3 capsule shell to obtain 100 mg.
Example 8
Taking 10g of folic acid, 100g of HPMC K100M 275g, 9g of sodium bicarbonate and 6g of magnesium stearate, uniformly mixing, controlling the hardness to be 2.0-5.0 kg, pressing the mixture into folic acid micro-tablets with the diameter of 4.0mm by a micro-tablet pressing machine, filling the micro-tablets into capsules, and obtaining the folic acid content of 5.0mg in each capsule according to 150mg micro-tablets in each capsule. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 8.
TABLE 8
(1) Micronizing folic acid raw material medicine, and controlling the particle size D of the raw material medicine90Controlling the particle size to be 5-20 mu m, and weighing the raw and auxiliary materials according to the formula.
(2) Sequentially adding folic acid, HPMC K100M and sodium bicarbonate into a V-shaped stirring mixer, and stirring at 80rpm for 20 min;
(3) transferring the mixed materials into a three-dimensional mixer, adding magnesium stearate according to the prescription amount, and rotating at a speed: 13rpm for 5 min.
(4) Tabletting: and (3) pressing 4.0mm micro tablets by using a micro tablet press, wherein the hardness is controlled to be 2.0-5.0 kg.
(5) Filling: and 3# capsule shells are adopted for filling.
Comparative example 1:
taking 10g of folic acid, HPMC K1500262 g, 25g of sodium bicarbonate and 3g of silicon dioxide, uniformly mixing, controlling the hardness to be 2.5-5.0 kg, and pressing into folic acid tablets with the weight of 150mg to obtain folic acid tablets with the folic acid content of 5.0mg per tablet. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 9.
TABLE 9
Comparative example 2:
taking 20g of folic acid, 235.5g of hydroxypropyl cellulose (HPC), 25g of crospovidone (pvpp), 15g of calcium carbonate and 4.5g of magnesium stearate, uniformly mixing, controlling the hardness to be 2.5-5.0 kg, and pressing into folic acid tablets with the weight of 150mg to obtain folic acid containing 10mg of folic acid in each tablet. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 10.
Watch 10
Comparative example 3:
taking 10g of folic acid, K150273.5g of HPMC and 15g of calcium carbonate, uniformly mixing, adding a proper amount of water, preparing a soft material, adding the soft material into a WL350 extrusion spheronizer, controlling the size of a sieve pore and the spheronization condition to obtain a pellet with the diameter of about 2.0mm, drying at 40-50 ℃, respectively sieving with a 10-mesh sieve and a 14-mesh sieve to obtain a pellet with the slow release effect and the size of 1.4-2 mm, and adding magnesium stearate. Filling 150mg of micro-pills into each capsule to obtain 5.0mg of folic acid in each capsule. The dissolution rate and the rising time were measured in the dark using 900ml of 0.1mol/LHCl medium, and the results are shown in Table 11.
TABLE 11
Effect example 1
TABLE 12 sustained Release formulations in vitro Release time
And (3) analyzing experimental result data:
the drug release time of the sustained release preparations of examples 1 to 8 reached the designed 6-hour release time, and the drug release time of the comparative examples did not reach the design requirements, and the significant difference was found (P < 0.05). The bleaching time of the embodiment is obviously superior to that of the medicaments provided by the comparative examples 1-3, the embodiment has good bleaching effect and lasting floating time, and is obviously different from the comparative examples (P < 0.05).
And (4) conclusion:
according to the analysis of experimental data, the rising time in gastric juice is obviously shorter than that of a comparative example, the gastric juice can float for a long time, and the gastric juice has good slow release performance, and can obviously prolong the retention time of the drug in the stomach. Compared with the common preparation, the sustained-release preparation provided by the invention has more lasting pharmacological action and more obvious action effect.
Meanwhile, in the matrix tablet preparation process and the pellet preparation process, the particles or pellet cores have the advantages of small density, adjustable particle size and the like, so that the preparation with short floating time and long floating time can be easily prepared. The preparation method is simple and can realize industrial production.
Effect example 2
Since the release is usually slower for general sustained release preparations, but the best site for drug absorption is generally located in the duodenum and anterior small intestine, general sustained release preparations reduce the bioavailability of the drug, or are equally bioavailable, and are unlikely to have higher bioavailability than general sustained release preparations. Folic acid needs to be biologically converted into 5-methyl tetrahydrofolic acid to be effective after oral administration, but the folic acid sustained-release preparation of the invention has faster 5-methyl tetrahydrofolic acid level increase compared with a normal-release preparation so as to greatly exceed the original purpose of folic acid sustained-release preparation design, but the over-expected result can bring extra clinical benefit, namely, less drug is needed for reaching the same clinical curative effect, or better clinical benefit is obtained for the same drug.
In order to verify the clinical significance of the invention, an animal model is designed to verify the creativity of the invention, and the creativity is as follows: taking 40 SD rats, dividing into 2 groups, dividing into a control group and an experimental group, wherein each group comprises 20 SD rats, taking 1ml of blood from tail vein (more than two rats can be taken for mixing), measuring 5-methyltetrahydrofolate in blood serum by enzyme-linked immunosorbent assay, measuring homocysteine level by enzyme method (5 samples in total), and marking the SD rats as 0 week level; feeding feed with folic acid content of 0mg/kg and succinylsulfamothiazole content of 1%, measuring blood serum folic acid concentration homocysteine level after feeding for 6 weeks, and marking as 6 weeks; 3.6mg/kg of methotrexate was gavaged once a week from week 7, 0.2mg/kg of folic acid suspension (sri-an 0.4mg folic acid tablet 1 tablet (125 mg/tablet) was ground to about 62.5mg/kg of powder and suspended to 1ml with water) was gavaged once a day for the control group, 20mg/kg of the sustained-release pellet of example 7 (containing 0.2mg folic acid) was given once a day for the experimental group, and then the rat serum levels of 5-methyltetrahydrofolic acid (5-MTHF) and homocysteine were measured once a week, labeled 7, 8 and 9, 9 … … 14 weeks, respectively, and the results are shown in Table 13.
TABLE 13 plasma folate and homocysteine levels in rats at different stages (n ═ 5)
From the above table, it can be seen that in 0 weeks, there is no significant difference in the serum 5-methyltetrahydrofolate levels and homocysteine levels of the two groups of rats tested; after the feed which is free of folic acid and contains the intestinal bacterium folic acid synthesis inhibitor is fed for 6 weeks, the 5-methyltetrahydrofolate level of blood plasma is obviously reduced, a hyperhomocysteinemia model is formed at the same time, and the 5-methyltetrahydrofolate level and the homocysteine level of blood serum of two groups of rats which are pre-tested have no obvious difference; after two groups of rats continue to feed methotrexate once a week to cause a similar human folic acid metabolic disorder model, a control group of rats feed a common preparation suspension of folic acid which is equivalent to 0.2mg/kg folic acid every day, and an experimental group feeds a sustained-release preparation which is equivalent to 0.2mg/kg folic acid, namely two groups of rats have consistent administration dosage; by measuring the serum 5-methyltetrahydrofolate level and the homocysteine level of the rats every week, the serum 5-methyltetrahydrofolate level of the sustained-release preparation group rises faster than that of the common preparation suspension of the folic acid from the first week as shown in the table above, and the two groups of rats have statistically significant difference until the serum level of the two groups of rats is consistent from the 12 th week (namely, the 6 th week after administration); meanwhile, the corresponding rat homocysteine level shows more rapid decline from the beginning of administration in the sustained-release preparation group, and the level does not tend to be consistent until two weeks at 11 weeks (namely 5 weeks of administration), so that the sustained-release preparation group has better curative effect.
The folic acid sustained-release preparations prepared in examples 1 to 6 and 8 were subjected to the above-described experiments under the same conditions, and the results of the experiments were not significantly different from the effect data of the sustained-release preparation prepared in example 7 (P > 0.05). The slow release preparation provided by the invention has better curative effect compared with the common folic acid suspension group.
Another 40 SD rats are divided into 2 groups, and the model is made according to the method to obtain the rat model with low-folate hyperhomocysteine. 3.6mg/kg of methotrexate was gavaged once a week from week 7, 0.2mg/kg of folic acid suspension (sri-an 0.4mg folic acid tablet 1 tablet (125 mg/tablet) was ground to about 62.5mg/kg of powder and suspended to 1ml with water) was gavaged once a day for the control group, 25mg/kg of the sustained-release pellet of example 6 (containing 0.1mg folic acid) was given once a day for the experimental group, and then the rat serum levels of 5-methyltetrahydrofolic acid (5-MTHF) and homocysteine were measured once a week, labeled 7, 8 and 9, 9 … … 14 weeks, respectively, and the results are shown in Table 14.
TABLE 14 plasma folate and homocysteine levels in rats at different stages (n ═ 5)
From the above table, it can be seen that the administration dosage of the sustained-release pellet group is 50% of that of the control group (silian folic acid tablet), and the 5-methyltetrahydrofolic acid level is improved and the homocysteine reduction capability is consistent.
The folic acid sustained-release preparations prepared in examples 1 to 5 and 7 to 8 were subjected to the above-mentioned experiments under the same conditions, and the results of the experiments were not significantly different from the effect data of the sustained-release preparation prepared in example 6 (P > 0.05). The folic acid sustained-release preparation group is proved to have double curative effect in a low-folic acid rat model, which further proves the creativity of the folic acid sustained-release preparation.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The folic acid slow release composition is characterized by comprising the following components in parts by weight:
0.75 to 6.67 parts by weight of folic acid
60-92 parts by weight of slow release material
3-30 parts of a bleaching agent;
the slow release material comprises one or a mixture of more than two of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer and chitosan;
the bleaching agent comprises one or a mixture of more than two of carbonate, high polymer material, hexadecanol, octadecanol, stearic acid and glyceryl monostearate.
2. The folic acid sustained-release composition of claim 1, wherein the carbonate comprises one or a mixture of two of sodium bicarbonate, sodium carbonate, magnesium carbonate, and calcium carbonate; the polymer material comprises crospovidone.
3. The folic acid sustained-release composition according to claim 1 or 2, which comprises the following components in parts by weight:
folic acid 3.33 weight portions
Sustained release material 85.17 weight portions
10 parts of bleaching agent.
4. Use of a folic acid delayed release composition according to anyone of claims 1 to 3 for the preparation of a folic acid delayed release formulation.
5. A folic acid sustained release preparation comprising the folic acid sustained release composition according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
6. The folic acid sustained-release preparation of claim 5, wherein the auxiliary material comprises one or a mixture of more than two of talcum powder, aerosil and magnesium stearate.
7. The folic acid sustained-release preparation of claim 6, which comprises the following components in parts by weight:
8. the folic acid sustained-release preparation of claim 6, which comprises the following components in parts by weight:
9. the folic acid sustained-release preparation of any one of claims 5 to 8, wherein the dosage form comprises one or more of folic acid sustained-release matrix tablets, folic acid sustained-release pellets, folic acid sustained-release capsules or folic acid sustained-release micro-tablets;
the preparation method of the folic acid sustained-release matrix tablet comprises the following steps: mixing folic acid with the slow release material, the bleaching agent and the anti-sticking agent, and tabletting by a direct powder tabletting process or adding a binding agent for wet granulation to prepare the folic acid slow release matrix tablet;
the preparation method of the folic acid sustained-release pellet comprises the following steps: mixing folic acid with the sustained-release material, adding wetting agent to make soft mass, making into pellet, and drying; preparing folic acid sustained-release pellets;
or mixing folic acid with the sustained-release material and the bleaching agent, mixing with the wetting agent, preparing soft material, preparing pellet, and drying to obtain folic acid sustained-release pellet;
the preparation method of the folic acid sustained-release capsule comprises the following steps: mixing folic acid with the sustained-release material, adding wetting agent to make soft mass, making into pellet, and drying; coating the bleaching agent and the sustained-release material, and filling a capsule to obtain a folic acid sustained-release pellet capsule;
or mixing folic acid with the sustained release material and the bleaching agent, mixing with wetting agent, preparing soft material, preparing pellet, drying to obtain folic acid sustained release pellet, and encapsulating to obtain folic acid sustained release pellet capsule;
the preparation method of the folic acid sustained-release micro-tablet comprises the following steps: mixing folic acid with the sustained release material, the bleaching agent and magnesium stearate, and tabletting to obtain the final product.
10. Use of the folic acid delayed release composition according to any one of claims 1 to 3 or the folic acid delayed release formulation according to any one of claims 5 to 9 for the preparation of a medicament for the prophylaxis and/or treatment of megaloblastic anemia, fetal neural tube malformations, folic acid deficiency or other diseases caused by a relative deficiency of folic acid; the other diseases include one or more of hyperhomocysteinemia, stroke, cognitive dysfunction.
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| CN115040489A (en) * | 2022-08-17 | 2022-09-13 | 北京罗诺强施医药技术研发中心有限公司 | Stable pharmaceutical composition with excellent consistency and process for preparing the same |
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| CN115040489B (en) * | 2022-08-17 | 2022-10-25 | 北京罗诺强施医药技术研发中心有限公司 | Stable pharmaceutical composition with excellent consistency and process for preparing the same |
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