CN110237046A - A kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule - Google Patents
A kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of L-5- methyl tetrahydrofolate micro-capsule, L-5- methyl tetrahydrofolate aqueous solution is added in shellac methanol solution by this method first, cause mutually to separate generation precipitating, to which L-5- methyl tetrahydrofolate is wrapped in shellac, form first layer micro-capsule, then film package is carried out to first layer micro-capsule with filmogen zeins and ethyl cellulose again, to form the L-5- methyl tetrahydrofolate micro-capsule with two layers of package, the stability of L-5- methyl tetrahydrofolate can be greatly improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule.
Background technique
Folic acid (folic acid) be also Vitamin B9, is a kind of water soluble vitamin.0.4 milligram of folic acid is for preventing tire
Youngster's neural tube malformation, ready-to-be mother just takes 0.4 milligram of folic acid during standby pregnant can decline Fetal neurotubules malformation rate 85%；5
Milligram folic acid can be used to treat female anemia, play the role of promoting juvenile cell in marrow mature, the mankind such as lack folic acid and can cause
Macrocytic anemia and leukopenia, are even more important to pregnant woman.
The biologically active form of folic acid in vivo is tetrahydrofolic acid (THF), and THF is in internal one carbon unit transfer enzyme system
Coenzyme, be by folic acid in the presence of vitamin C and NADH+, through generating dihydrofoilic acid under reduction of folates enzyme effect, then by two
Hydrogen reduction of folates enzymatic generates THF.THF can transmit one carbon unit, be the carrier of a carbon-based group, participate in pyrimidine, purine
Synthesis, can promote the generation of normal plasma cell.Such as L-5- methyl tetrahydrofolate carries methylene, methyl one carbon unit, shape
At 5,10- methylene tetrahydrofolate, 5-methyltetrahydrofolate (5-MTHF) etc..Wherein 5-MTHF is in conjunction with plasma protein in human body
Afterwards, mainly it is transported to liver storage.So when folic acid reductase is by some Drug inhibitions or folic acid deficiency, will affect folic acid to
The proper transition of L-5- methyl tetrahydrofolate (L-5-MTHF) causes huge children red thin to influence the maturation and development of haemocyte
Born of the same parents' property anaemia.
Folic acid mainly exists in a manner of L-5-MTHF in the blood and tissue of human body, participates in many lifes in human body
Change reaction.L-5-MTHF is the principal mode that folic acid plays a role in vivo, needs not move through complicated enzymatic reaction, so that it may
Directly it is absorbed and utilized by the body.At abroad, the report about L-5-MTHF has very much, but since itself has stability
Difference, it is sensitive to oxygen the defects of, therefore do not obtain widespread commercialization in production.
By literature search, domestic and foreign literature be there are no about L-5- methyl tetrahydrofolate micro-capsule and preparation method thereof at present
Report, also there are no L-5- methyl tetrahydrofolate micro-capsule launch at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule, the micro-capsules of this method preparation
Have many advantages, such as that stability is good, bioavilability is high, rate of release is controllable.
To achieve the above object, The technical solution adopted by the invention is as follows:
A kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule, comprising the following steps:
1) L-5- methyl tetrahydrofolate and amino acid are dissolved with water under nitrogen protection, are stirred to react in 10-20 DEG C
10-30min dissolves shellac with anhydrous methanol, and the shellac solution that weight concentration is 1-5% is made, then will be after above-mentioned reaction
Solution be slowly dropped in shellac solution, it is stirring while adding, will precipitation solid filter after be washed with water, obtain yellow solid
Powder；
2) zeins and ethyl cellulose 50-90% (being weight concentration) ethyl alcohol are dissolved, weight is made
Concentration is the mixed solution of 0.5-5%, and starch, dextrin, silica are then added into mixed solution and stirs evenly, will walk
The rapid yellow solid powder 1) obtained with a small amount of water dispersion and is added in mixed solution after mixing with antioxidant, is stirred evenly
After be spray-dried, up to L-5- methyl tetrahydrofolate micro-capsule after discharging,
Wherein, the weight proportion of each ingredient is:
Preferably, the weight proportion of each ingredient is:
Preferably, the amino acid is ornithine.
Preferably, the antioxidant is tert-butyl hydroquinone or ascorbic acid.
Preferably, the organic solvent is anhydrous methanol.
Preferably, the process conditions of the spray drying are 50-70 DEG C of temperature of charge, charging rate 1-5mL/min, are done
The dry time is 10-100min.
The present invention utilizes the dissolution characteristics of shellac, is soluble in the organic solvents such as methanol, ethyl alcohol, normal propyl alcohol according to it, almost
Insoluble in acidity to the property of neutral aqueous medium, L-5- methyl tetrahydrofolate aqueous solution is added in shellac methanol solution,
Cause mutually to separate generation precipitating, so that L-5- methyl tetrahydrofolate is wrapped in shellac, forms first layer micro-capsule.Then it uses again
Filmogen zeins and ethyl cellulose carry out film package to first layer micro-capsule, so that being formed has two layers of package
L-5- methyl tetrahydrofolate micro-capsule, the stability of L-5- methyl tetrahydrofolate can be greatly improved.
Wherein, L-5- methyl tetrahydrofolate is reacted with amino acid, mainly there are following three purposes, first is that in order to generate L-
5-methyltetrahydrofolate amino-acid salt, to improve the dissolubility of L-5- methyl tetrahydrofolate, to improve the biological utilisation of drug
Degree；Second is that it is more stable at the L-5- methyl tetrahydrofolate after salt, it is more difficult to be oxidized degradation；Third is that in order to reduce solution
PH separates L-5- methyl tetrahydrofolate aqueous solution preferably mutually with the generation of shellac methanol solution.
Wherein, it is found by experiment that, ornithine and other amino acid such as arginine, lysine, tyrosine, phenylalanine phase
Than L-5- methyl tetrahydrofolate property is most stable, degradation least easy to oxidize.
Wherein, antioxidant is added can further improve the stability of L-5- methyl tetrahydrofolate.
Wherein, the effect of starch is to improve the mobility of micro-capsule, increases the spray drying speed of micro-capsule；Dextrin has certain
Viscosity, the surface texture of micro-capsule can be improved, prevent its cracked；Silica has porous structure and hydrophobic property, adds
Hygroscopicity can not only be reduced by entering in micro-capsule, while there are also pores to act on, and fine and closely woven aperture is formed after being swollen micro-capsule in water, from
And make L-5- methyl tetrahydrofolate slow release, in addition, there are also the effects of lubrication for silica, micro-capsule surface more light can be made
Sliding, mobility is more preferable.
The beneficial effects of the present invention are:
Present invention reduces hygroscopicity of the L-5- methyl tetrahydrofolate in storage, improve L-5- methyl tetrahydrofolate
Stable content, can prevent its occur oxidative degradation, to improve the stability of drug.Invention also improves L-5- first
The bioavilability of base tetrahydrofolic acid has delayed the rate of release of drug.
Pellet regular shape prepared by the present invention is uniform, surface is smooth, good fluidity, and L-5- methyl tetrahydrofolate contains
Amount is high, embedding rate is high, provided preparation method simple process, and production cost is low.
Specific embodiment
The present invention is described in detail below by specific embodiment.
Embodiment 1
1) under nitrogen protection, 30g L-5- methyl tetrahydrofolate and 20g ornithine 200ml water are dissolved, in 15 DEG C
It is stirred to react 10min, 15g shellac is dissolved with anhydrous methanol, the shellac solution that weight concentration is 2% is made, it then will be above-mentioned
Solution after reaction is slowly dropped in shellac solution, stirring while adding, is washed with water after the solid of precipitation is filtered, is obtained Huang
Color solid powder；
2) 14g zeins and 70% ethyl alcohol of 7g ethyl cellulose are dissolved, it is 1.5% that weight concentration, which is made,
Then mixed solution is added 6g starch, 6g dextrin, 1g silica and is stirred evenly into mixed solution, step 1) is obtained
Yellow solid powder mixed with 1g ascorbic acid after with a small amount of water dispersion and be added in mixed solution, carry out after mixing evenly
Spray drying controls 60 DEG C of temperature of charge, charging rate 3mL/min, drying time 60min, up to L-5- methyl after discharging
Tetrahydrofolic acid micro-capsule.
The weight proportion of each ingredient is:
Micro-capsule is weighed, sample detection, L-5- methyl tetrahydrofolate content is 27.5%, embedding rate 86.0%.It will be sprayed
Microcapsule powder after drying is uniformly pasted on glass slide, blows away extra powder, with electron microscope observation encystation situation, knot
Fruit microcapsule granule rounding, surface is smooth, basic flawless, and micro-capsule is uniform in size.
Embodiment 2
1) under nitrogen protection, 30g L-5- methyl tetrahydrofolate and 30g ornithine 300ml water are dissolved, in 10 DEG C
It is stirred to react 30min, 10g shellac is dissolved with anhydrous methanol, the shellac solution that weight concentration is 1% is made, it then will be above-mentioned
Solution after reaction is slowly dropped in shellac solution, stirring while adding, is washed with water after the solid of precipitation is filtered, is obtained Huang
Color solid powder；
2) 10g zeins and 50% ethyl alcohol of 10g ethyl cellulose are dissolved, it is 5% that weight concentration, which is made,
Then mixed solution is added 3g starch, 3g dextrin, 2g silica and is stirred evenly into mixed solution, step 1) is obtained
Yellow solid powder mixed with 2g tert-butyl hydroquinone after with a small amount of water dispersion and be added in mixed solution, stir evenly
After be spray-dried, 50 DEG C of temperature of charge, charging rate 1mL/min, drying time 100min are controlled, up to L- after discharging
5-methyltetrahydrofolate micro-capsule.
Wherein, the weight proportion of each ingredient is:
Micro-capsule is weighed, sample detection, L-5- methyl tetrahydrofolate content is 24.7%, embedding rate 81.3%.
Embodiment 3
1) under nitrogen protection, 30g L-5- methyl tetrahydrofolate and 10g ornithine 100ml water are dissolved, in 20 DEG C
It is stirred to react 10min, 20g shellac is dissolved with anhydrous methanol, the shellac solution that weight concentration is 5% is made, it then will be above-mentioned
Solution after reaction is slowly dropped in shellac solution, stirring while adding, is washed with water after the solid of precipitation is filtered, is obtained Huang
Color solid powder；
2) 20g zeins and 90% ethyl alcohol of 5g ethyl cellulose are dissolved, it is 0.5% that weight concentration, which is made,
Then mixed solution is added 10g starch, 3g dextrin, 0.5g silica and is stirred evenly into mixed solution, step 1) is obtained
To yellow solid powder mixed with 1.5g ascorbic acid after with a small amount of water dispersion and be added in mixed solution, after mixing evenly
It is spray-dried, controls 70 DEG C of temperature of charge, charging rate 5mL/min, drying time 10min, up to L-5- after discharging
Methyl tetrahydrofolate micro-capsule,
Wherein, the weight proportion of each ingredient is:
Micro-capsule is weighed, sample detection, L-5- methyl tetrahydrofolate content is 25.3%, embedding rate 83.1%.
Test example
1. wettability test
Example 1 (lot number 0401), embodiment 2 (lot number 0402), embodiment 3 (lot number 0403) and common L-5- methyl
Tetrahydrofolic acid (lot number 0501) sample investigates raw material hygroscopicity, and hygroscopicity measuring method: accurate weighing about 2g sample is put into training
It supports in ware, is placed in and fills saturation NaSO4In the drier of solution (relative humidity 81%), balance 1 week at room temperature.After taking-up again
Secondary weighing, and hygroscopicity is calculated according to the following formula: hygroscopicity/%=absorption moisture weight (g)/sample weight (g) ×
100,1 hygroscopicity of embodiment is 23.33% as the result is shown, 2 hygroscopicity of embodiment is 25.15%, 3 hygroscopicity of embodiment is
28.25%, common L-5- methyl tetrahydrofolate hygroscopicity is 65.33%, and the L-5- methyl tetrahydrofolate hygroscopicity after micro-capsule is bright
It is aobvious to reduce.
2. stability test
Example 1-3L-5- methyl tetrahydrofolate micro-capsule and common L-5- methyl tetrahydrofolate sample carry out accelerated test
Control is investigated, and acceleration environment is 37 DEG C ± 2 DEG C, RH75% ± 5%, detects each sample L-5- methyl four respectively at 0,1,2, March
The content of hydrogen folic acid and calculating accounts for the percentage of initial content, to judge its stability, the results are shown in Table 1.
The accelerated stability test result of 1 L-5- methyl tetrahydrofolate micro-capsule of table
From accelerated test as can be seen that L-5- methyl tetrahydrofolate content has a declining tendency under acceleration conditions, from
Untreated L-5- methyl tetrahydro leaf is substantially better than by the L-5- methyl tetrahydrofolate that microencapsulation is handled from the point of view of downward trend
Hydrochlorate, and in embodiment 1 micro-capsule stability it is best.
Claims (6)
1. a kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule, it is characterised in that the following steps are included:
1) L-5- methyl tetrahydrofolate and amino acid are dissolved with water under nitrogen protection, are stirred to react 10- in 10-20 DEG C
30min dissolves shellac with organic solvent, and the shellac solution that weight concentration is 1-5% is made, then will be molten after above-mentioned reaction
Liquid is slowly dropped in shellac solution, stirring while adding, is washed with water after the solid of precipitation is filtered, is obtained yellow solid powder
End；
2) zeins and ethyl cellulose 50-90% ethyl alcohol are dissolved, the mixing that weight concentration is 0.5-5% is made
Then starch, dextrin, silica are added into mixed solution and stirs evenly, the yellow solid that step 1) is obtained for solution
Powder with a small amount of water dispersion and is added in mixed solution after mixing with antioxidant, is spray-dried after mixing evenly, out
Up to L-5- methyl tetrahydrofolate micro-capsule after material,
Wherein, the weight proportion of each ingredient is:
2. the preparation method of L-5- methyl tetrahydrofolate micro-capsule as described in claim 1, which is characterized in that the weight of each ingredient is matched
Than being:
3. the preparation method of L-5- methyl tetrahydrofolate micro-capsule as claimed in claim 1 or 2, it is characterised in that: the amino acid
For ornithine.
4. the preparation method of L-5- methyl tetrahydrofolate micro-capsule as claimed in claim 1 or 2, it is characterised in that: described anti-oxidant
Agent is tert-butyl hydroquinone or ascorbic acid.
5. the preparation method of L-5- methyl tetrahydrofolate micro-capsule as claimed in claim 1 or 2, it is characterised in that: described organic molten
Agent is anhydrous methanol.
6. the preparation method of L-5- methyl tetrahydrofolate micro-capsule as claimed in claim 1 or 2, it is characterised in that: described spraying dry
Dry process conditions are 50-70 DEG C of temperature of charge, charging rate 1-5mL/min, drying time 10-100min.
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