CN110237046B - Preparation method of L-5-methyltetrahydrofolic acid microcapsules - Google Patents
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Abstract
The invention discloses a preparation method of L-5-methyltetrahydrofolic acid microcapsules, which comprises the steps of adding an L-5-methyltetrahydrofolic acid aqueous solution into a shellac methanol solution, causing phase separation to generate precipitation, coating L-5-methyltetrahydrofolic acid in shellac to form a first layer of microcapsules, and then coating the first layer of microcapsules with film-forming materials of zein and ethyl cellulose to form L-5-methyltetrahydrofolic acid microcapsules with two layers of coatings, wherein the stability of L-5-methyltetrahydrofolic acid can be greatly improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of L-5-methyltetrahydrofolic acid microcapsules.
Background
Folic acid, also known as vitamin B9, is a water-soluble vitamin. 0.4 mg of folic acid is used for preventing the fetal neural tube deformity, and the fetal neural tube deformity rate can be reduced by 85 percent by taking 0.4 mg of folic acid by an expectant mother during the pregnancy preparation period; 5 mg folic acid can be used for treating female anemia, has the function of promoting the maturation of immature cells in bone marrow, and is especially important for pregnant women, such as megaloblastic anemia and leukopenia caused by folic acid deficiency.
The bioactive form of folic acid in vivo is tetrahydrofolic acid (THF), which is a coenzyme in the one-carbon unit transferase system in vivo, and is produced by folic acid in the presence of vitamin C and NADH + via the action of folate reductase to produce dihydrofolic acid, and then THF is produced by dihydrofolate reductase. THF can transmit one-carbon unit, is a carrier of one-carbon group, participates in the synthesis of pyrimidine and purine, and can promote the generation of normal blood cells. For example, L-5-methyltetrahydrofolic acid carries a methylene group, a methyl group, etc. to form 5, 10-methylenetetrahydrofolic acid, 5-methyltetrahydrofolic acid (5-MTHF), etc. Wherein the 5-MTHF is combined with plasma protein in human body and is mainly transported to liver for storage. Therefore, when the folate reductase is inhibited by some drugs or is deficient in folate, the normal conversion of folate to L-5-methyltetrahydrofolate (L-5-MTHF) is affected, and therefore the maturation and development of blood cells are affected, and megaloblastic anemia is caused.
Folic acid exists mainly in the blood and tissues of the human body in the form of L-5-MTHF, and participates in many biochemical reactions in the human body. L-5-MTHF is the main form of folic acid which plays a role in the body and can be directly absorbed and utilized by the human body without complex enzymatic reactions. In foreign countries, there are many reports on L-5-MTHF, but because it has the defects of poor stability and sensitivity to oxygen, it has not been widely industrialized in production.
Through literature search, at present, no report on L-5-methyltetrahydrofolate microcapsules and a preparation method thereof is found in domestic and foreign literatures, and no products of the L-5-methyltetrahydrofolate microcapsules are on the market at home and foreign places.
Disclosure of Invention
The invention aims to provide a preparation method of L-5-methyltetrahydrofolic acid microcapsules, and the microcapsules prepared by the method have the advantages of good stability, high bioavailability, controllable release speed and the like.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of L-5-methyltetrahydrofolic acid microcapsules comprises the following steps:
1) under the protection of nitrogen, dissolving L-5-methyltetrahydrofolic acid and amino acid in water, stirring and reacting at 10-20 ℃ for 10-30min, dissolving shellac in anhydrous methanol to prepare shellac solution with the weight concentration of 1-5%, slowly dripping the reacted solution into the shellac solution while stirring, filtering the precipitated solid and washing with water to obtain yellow solid powder;
2) dissolving zein and ethyl cellulose with 50-90% (weight concentration) ethanol to obtain a mixed solution with the weight concentration of 0.5-5%, adding starch, dextrin and silicon dioxide into the mixed solution, stirring uniformly, dispersing the yellow solid powder obtained in step 1) and antioxidant in a small amount of water, adding the mixture into the mixed solution, stirring uniformly, spray drying, discharging to obtain L-5-methyltetrahydrofolic acid microcapsule,
wherein the weight ratio of each component is as follows:
preferably, the weight ratio of each component is as follows:
preferably, the amino acid is ornithine.
Preferably, the antioxidant is tert-butylhydroquinone or ascorbic acid.
Preferably, the organic solvent is anhydrous methanol.
Preferably, the spray drying process conditions are that the material temperature is 50-70 ℃, the feeding speed is 1-5mL/min, and the drying time is 10-100 min.
According to the invention, by utilizing the dissolution characteristic of shellac, according to the property that shellac is easily soluble in organic solvents such as methanol, ethanol and n-propanol and is almost insoluble in acidic to neutral aqueous media, L-5-methyltetrahydrofolic acid aqueous solution is added into shellac methanol solution to cause phase separation to generate precipitation, so that L-5-methyltetrahydrofolic acid is wrapped in shellac to form a first layer of microcapsule. Then the first layer of microcapsule is coated with film forming materials of zein and ethyl cellulose to form two layers of L-5-methyltetrahydrofolic acid microcapsules, which can greatly improve the stability of L-5-methyltetrahydrofolic acid.
The reaction of L-5-methyltetrahydrofolic acid and amino acid has three main purposes, namely, the reaction is used for generating L-5-methyltetrahydrofolic acid amino acid salt so as to improve the solubility of L-5-methyltetrahydrofolic acid and further improve the bioavailability of the medicine; secondly, the salified L-5-methyltetrahydrofolic acid is more stable and is less prone to oxidative degradation; thirdly, the pH value of the solution is reduced, so that the L-5-methyl tetrahydrofolic acid aqueous solution is better separated from the shellac methanol solution.
Among them, ornithine is found by experiments to be the most stable and least susceptible to oxidative degradation compared with other amino acids such as arginine, lysine, tyrosine and phenylalanine.
Wherein, the stability of the L-5-methyltetrahydrofolic acid can be further improved by adding the antioxidant.
Wherein, the starch has the functions of improving the fluidity of the microcapsule and increasing the spray drying speed of the microcapsule; dextrin has certain viscosity, can improve the surface structure of the microcapsule, prevent it from appearing crackle; the silicon dioxide has a porous structure and a hydrophobic characteristic, can reduce hygroscopicity when added into the microcapsule, has a pore-forming effect at the same time, and enables the microcapsule to form a fine pore diameter after swelling in water, so that the L-5-methyltetrahydrofolic acid is slowly released, and in addition, the silicon dioxide has a lubricating effect, so that the surface of the microcapsule is smoother and the flowability is better.
The invention has the beneficial effects that:
the invention reduces the hygroscopicity of the L-5-methyltetrahydrofolic acid in storage, improves the content stability of the L-5-methyltetrahydrofolic acid, and can prevent the L-5-methyltetrahydrofolic acid from oxidative degradation, thereby improving the stability of the medicine. The invention also improves the bioavailability of the L-5-methyltetrahydrofolic acid and delays the release speed of the medicine.
The pellet prepared by the invention has the advantages of regular and uniform shape, smooth surface, good fluidity, high L-5-methyltetrahydrofolic acid content and high embedding rate, and the provided preparation method has simple process and low production cost.
Detailed Description
The present invention will be described in detail below with reference to specific examples.
Example 1
1) Under the protection of nitrogen, dissolving 30g L-5-methyltetrahydrofolic acid and 20g ornithine by 200ml water, stirring and reacting for 10min at 15 ℃, dissolving 15g shellac by absolute methanol to prepare shellac solution with weight concentration of 2%, then slowly dripping the reacted solution into the shellac solution while stirring, filtering the precipitated solid and washing by water to obtain yellow solid powder;
2) dissolving 14g of zein and 7g of ethyl cellulose by using 70% ethanol to prepare a mixed solution with the weight concentration of 1.5%, then adding 6g of starch, 6g of dextrin and 1g of silicon dioxide into the mixed solution, uniformly stirring, dispersing the yellow solid powder obtained in the step 1) and 1g of ascorbic acid by using a small amount of water after mixing, adding the mixture into the mixed solution, uniformly stirring, carrying out spray drying, controlling the temperature of the material at 60 ℃, the feeding speed at 3mL/min, the drying time at 60min, and discharging to obtain the L-5-methyltetrahydrofolic acid microcapsule.
The weight ratio of each component is as follows:
the microcapsules were weighed, sampled and tested, and the content of L-5-methyltetrahydrofolate was 27.5% and the encapsulation rate was 86.0%. The spray-dried microcapsule powder is uniformly adhered on a glass slide, redundant powder is blown off, and the encapsulation condition is observed by an electron microscope, so that the microcapsule particles are round, the surface is smooth, cracks are basically avoided, and the size of the microcapsule is uniform.
Example 2
1) Under the protection of nitrogen, dissolving 30g L-5-methyltetrahydrofolic acid and 30g ornithine by 300ml water, stirring and reacting for 30min at 10 ℃, dissolving 10g shellac by absolute methanol to prepare shellac solution with weight concentration of 1%, then slowly dripping the reacted solution into the shellac solution while stirring, filtering the precipitated solid and washing by water to obtain yellow solid powder;
2) dissolving 10g of zein and 10g of ethyl cellulose by using 50% ethanol to prepare a mixed solution with the weight concentration of 5%, then adding 3g of starch, 3g of dextrin and 2g of silicon dioxide into the mixed solution, uniformly stirring, dispersing the yellow solid powder obtained in the step 1) and 2g of tert-butylhydroquinone in a small amount of water after mixing, adding the mixture into the mixed solution, uniformly stirring, carrying out spray drying, controlling the material temperature at 50 ℃, the feeding speed at 1mL/min, the drying time at 100min, and discharging to obtain the L-5-methyltetrahydrofolic acid microcapsule.
Wherein the weight ratio of each component is as follows:
the microcapsules are weighed, sampled and detected, the content of the L-5-methyltetrahydrofolic acid is 24.7 percent, and the embedding rate is 81.3 percent.
Example 3
1) Under the protection of nitrogen, dissolving 30g L-5-methyltetrahydrofolic acid and 10g ornithine by 100ml water, stirring and reacting for 10min at 20 ℃, dissolving 20g shellac by absolute methanol to prepare shellac solution with weight concentration of 5%, then slowly dripping the reacted solution into the shellac solution while stirring, filtering the precipitated solid and washing by water to obtain yellow solid powder;
2) dissolving 20g of zein and 5g of ethyl cellulose by 90% ethanol to prepare a mixed solution with the weight concentration of 0.5%, then adding 10g of starch, 3g of dextrin and 0.5g of silicon dioxide into the mixed solution and uniformly stirring, dispersing the yellow solid powder obtained in the step 1) and 1.5g of ascorbic acid by a small amount of water after mixing, adding the mixture into the mixed solution, uniformly stirring, carrying out spray drying, controlling the temperature of the material at 70 ℃, the feeding speed at 5mL/min, the drying time at 10min, discharging to obtain L-5-methyltetrahydrofolic acid microcapsules,
wherein the weight ratio of each component is as follows:
the microcapsules were weighed, sampled and tested, and the content of L-5-methyltetrahydrofolate was 25.3%, and the encapsulation rate was 83.1%.
Test examples
1. Moisture absorption test
Samples of example 1 (batch 0401), example 2 (batch 0402), example 3 (batch 0403) and ordinary L-5-methyltetrahydrofolic acid (batch 0501) were taken and the hygroscopicity of the material was examined as follows: about 2g of the sample was precisely weighed, placed in a petri dish, and placed in a container containing saturated NaSO4The solution was equilibrated at room temperature in a desiccator (81% relative humidity) for 1 week. Weighing again after taking out, and calculating the hygroscopicity according to the following formula: the results of moisture absorption/% (weight (g) of absorbed water)/weight (g) of sample) × 100 show that the moisture absorption of example 1 was 23.33%, the moisture absorption of example 2 was 25.15%, the moisture absorption of example 3 was 28.25%, the moisture absorption of ordinary L-5-methyltetrahydrofolic acid was 65.33%, and the moisture absorption of microencapsulated L-5-methyltetrahydrofolic acid was significantly reduced.
2. Stability test
The stability of the microcapsules of example 1-3L-5-methyltetrahydrofolate and the samples of common L-5-methyltetrahydrofolate were evaluated by accelerated test control under 37 ℃. + -. 2 ℃ and RH 75%.
TABLE 1 accelerated stability test results of L-5-methyltetrahydrofolate beadlets
Accelerated tests show that the content of the L-5-methyltetrahydrofolic acid is reduced under accelerated conditions, and the microencapsulated L-5-methyltetrahydrofolic acid is obviously superior to untreated L-5-methyltetrahydrofolic acid salt from the aspect of reduced content, and the stability of the microcapsule in example 1 is the best.
Claims (5)
1. A preparation method of L-5-methyltetrahydrofolic acid microcapsules is characterized by comprising the following steps:
1) under the protection of nitrogen, dissolving L-5-methyltetrahydrofolic acid and ornithine in water, stirring and reacting at 10-20 ℃ for 10-30min, dissolving shellac in an organic solvent to prepare shellac solution with the weight concentration of 1-5%, slowly dripping the reacted solution into the shellac solution while stirring, filtering the precipitated solid, and washing with water to obtain yellow solid powder;
2) dissolving zein and ethyl cellulose with 50-90% ethanol to prepare a mixed solution with the weight concentration of 0.5-5%, then adding starch, dextrin and silicon dioxide into the mixed solution and stirring uniformly, dispersing the yellow solid powder obtained in the step 1) and an antioxidant with a small amount of water after mixing, adding the mixture into the mixed solution, stirring uniformly, carrying out spray drying, discharging to obtain L-5-methyltetrahydrofolic acid microcapsules,
wherein the weight ratio of each component is as follows:
2. the method for preparing L-5-methyltetrahydrofolate microcapsules according to claim 1, wherein the weight ratio of each component is as follows:
3. a method for preparing L-5-methyltetrahydrofolate beadlets according to claim 1 or 2, wherein: the antioxidant is tert-butyl hydroquinone or ascorbic acid.
4. A method for preparing L-5-methyltetrahydrofolate beadlets according to claim 1 or 2, wherein: the organic solvent is absolute methanol.
5. A method for preparing L-5-methyltetrahydrofolate beadlets according to claim 1 or 2, wherein: the spray drying process conditions are that the material temperature is 50-70 ℃, the feeding speed is 1-5mL/min, and the drying time is 10-100 min.
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