CN109730323A - The oxide of iron, ferrous salt and/or combination thereof object are improving the application in folic acid stability - Google Patents
The oxide of iron, ferrous salt and/or combination thereof object are improving the application in folic acid stability Download PDFInfo
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- CN109730323A CN109730323A CN201910221749.1A CN201910221749A CN109730323A CN 109730323 A CN109730323 A CN 109730323A CN 201910221749 A CN201910221749 A CN 201910221749A CN 109730323 A CN109730323 A CN 109730323A
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- folic acid
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- oxide
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- ferrous salt
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Abstract
The present invention relates to field of biotechnology, in particular to composition more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both is improving the application in folic acid stability.Result of study shows, folic acid and iron oxide yellow and brown color ferrous succinate, the ferrous salts compatibility such as ferrous fumarate, can conspicuousness improve folic acid to the stability of light.
Description
Technical field
The present invention relates to field of biotechnology, in particular to the oxide of iron, ferrous salt and/or oxide containing iron,
Composition more than the two in ferrous salt or molysite or both is improving the application in folic acid stability.
Background technique
Folic acid belongs to one of B family vitamin.Folic acid is reduced into vivo as tetrahydrofolic acid, participates in a variety of methyl of body
The coenzyme of change approach can also participate in the biology conversion of a variety of amino acid, and body, which lacks, often betides dietary int ake deficiency, such as
It is malnutritive；Malabsorption, such as tropical diarrhea；Body utilizes increase, such as pregnancy hemolytic anemia；It loses and increases, such as blood
Dialysis etc.；So folic acid is usually used in preventing newborn's neural tube malformation before and after standby pregnant, the huge juvenile cell of long-term folic acid deficiency is poor
Blood.Folic acid is now widely used in medical field, and such as the 0.4mg Couteat of Folic Acid of market sale is used for neonatal nerve at home at present
Pipe deformity, 5mg Couteat of Folic Acid are used for megaloblastic anemia, also have in foreign countries and are used for folic acid deficiency for folic acid as dietary supplement,
Suitable folic acid is added such as in Follow Up Formula, food.
But folic acid is pteroylglutamic acid structure, is made of pterin, p-aminobenzoic acid and glutamic acid, has photo-labile
Property, especially light (especially ultraviolet light and visible light), it is wet it is existing under the conditions of be easier to degrade, lead to many products
When carrying out quality control by Chinese Pharmacopoeia, related substance (impurity A, N- (4- amino benzoyl)-Pidolidone) obviously exceeds
Limit standard (≤1%).
Thus in the product of foreign countries' listing, in order to improve stability and the effect phase of product, not only in the prescription of product and
It is improved in technique, the 0.4mg Couteat of Folic Acid of such as French Sino phenanthrene listing uses direct powder compression, avoids the light of folic acid wet
Degradation, even if the standard of its light degradation impurity A in this way is less than 2% (being far higher by standard≤1.0% of Chinese Pharmacopoeia).To understand
The certainly light degradation problem of folic acid, the impurity A after reducing its light degradation is horizontal, and there are many researchs and patent to be reported it,
Such as during folic acid fortified flour saving and processing folic acid stability research (Jia Min, Chinese food and nutrition, 2018,24
In (3:18-20), by the storage condition of optimization, 28 days, 25 DEG C of folic acid of room temperature had dropped (12.38% ± 1.81%).?
Secondary width etc. investigated the preparation process condition of Couteat of Folic Acid to the stability of folic acid influence (Zhang Zhongkuan etc., technique and preparation,
2018,11:41-45), the results showed that, even if sample accelerates its largest single impurity in June to reach using the process conditions after optimization
To 0.6% or more level, close to 2015 editions upper limits of Chinese Pharmacopoeia.Patent " a kind of powder coating folic acid and preparation method thereof "
The stability that folic acid is improved in (application number 201410844331.3) is prepared using the method that powder coats, although
Final products can properly increase product stability, but its preparation process is more complex, cause preparation cost high, in practical application
In, practicability especially is lacked to the higher field of food of cost requirement.In a kind of patent " side for enhancing folic acid photostability
In method " (application number 201610921126.1), one kind " hydroxy cinnamic acid derivative " Lai Tigao folic acid is added in folic acid to light
Stability, be remarkably improved the stability of folic acid as the result is shown, but in this patent exist a significant defect, first is that
The safety risks of hydroxy cinnamic acid derivative, second is that hydroxymyristic acid derivative belongs to a kind of antioxidant, in protection folic acid
Not by during photodegradative, by light degradation, the Product safety problem values after light degradation must continue to study for itself.
Therefore it provides the stability for improving folic acid has important practical significance.
Summary of the invention
In view of this, the present invention provide the oxide of iron a kind of, ferrous salt and/or oxide containing iron, ferrous salt and
The composition of molysite is improving the application in folic acid stability.The present invention provides the folic acid groups that can increase folic acid photostability
Object is closed, this composition can be used for preparing drug, or be added in food, significantly improve folic acid to the stability of light.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Or both more than composition improve folic acid stability in application；The oxide of the iron is the iron of yellow or brown color
Oxide；The ferrous salt is the ferrous salt of yellow or brown color.
The present invention also provides two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Application of the composition in food of the preparation containing folic acid, health care product or drug more than person or both；The ferrous salt is Huang
The ferrous salt of color or brown color.
In some specific embodiments of the invention, the oxide of the iron is iron oxide yellow and/or di-iron trioxide,
The ferrous salt includes the mixture of one or more of ferrous succinate or ferrous fumarate.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition can for iron oxide form composition, or ferrous salt composition composition, also
It can be the oxide of iron and the composition of ferrous salt, can also be the oxide of iron and the composition of molysite, can also be Asia
The composition of molysite and molysite can also be the composition of the oxide of iron, ferrous salt or molysite.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition be the iron black pigment being made of ferrous oxide and di-iron trioxide, wherein ferrous oxide and three aoxidize
The molar ratio of two iron is (0.2~0.8): (0.8~0.2)；Preferably, ferrous oxide and di-iron trioxide molar ratio are
0.33:0.67.
In some specific embodiments of the invention, the oxide of the iron is iron oxide yellow and/or di-iron trioxide,
The ferrous salt includes the mixture of one or more of ferrous succinate or ferrous fumarate.Specifically, described contain
The composition for having the two in the oxide, ferrous salt or molysite of iron or both or more is the medicine of medicinal iron oxide yellow, comprehensive yellow
With ferrous succinate, the medicinal ferrous fumarate of brown color or medicinal iron oxide black (di-iron trioxide/ferrous oxide mixture)
One or both of more than mixture.
In some specific embodiments of the invention, the mass ratio of the folic acid and the iron oxide yellow is 1:(0.05
~20)；
The mass ratio of the folic acid and the ferrous succinate is 1:(0.05~20)；
The mass ratio of the folic acid and the ferrous fumarate is 1:(0.05~20)；
10 μm of partial size < of the oxide of the iron, ferrous salt.
The present invention also provides composition, more than the two in oxide, ferrous salt including iron or molysite or both
Combination；The oxide of the iron is the oxide of the iron of yellow or brown color；The ferrous salt is the ferrous iron of yellow or brown color
Salt.
In some specific embodiments of the invention, the oxide of the iron is iron oxide yellow and/or di-iron trioxide,
The ferrous salt includes two or more the mixture in ferrous succinate or ferrous fumarate.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition can for iron oxide form composition, or ferrous salt composition composition, also
It can be the oxide of iron and the composition of ferrous salt, can also be the oxide of iron and the composition of molysite, can also be Asia
The composition of molysite and molysite can also be the composition of the oxide of iron, ferrous salt or molysite.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition be the iron black pigment being made of ferrous oxide and di-iron trioxide, wherein ferrous oxide and three aoxidize
The molar ratio of two iron is (0.2~0.8): (0.8~0.2)；Preferably, ferrous oxide and di-iron trioxide molar ratio are
0.33:0.67.
The present invention also provides folate compositions comprising folic acid and composition provided by the invention；The composition is
Combination more than the two in oxide, ferrous salt containing iron or molysite or both；The oxide of the iron is yellow or palm fibre
The oxide of the iron of yellow；The ferrous salt is the ferrous salt of yellow or brown color；The oxide of the iron be iron oxide yellow and/
Or di-iron trioxide, the ferrous salt include two or more the mixture in ferrous succinate or ferrous fumarate.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition can for iron oxide form composition, or ferrous salt composition composition, also
It can be the oxide of iron and the composition of ferrous salt, can also be the oxide of iron and the composition of molysite, can also be Asia
The composition of molysite and molysite can also be the composition of the oxide of iron, ferrous salt or molysite.
The two in some specific embodiments of the invention, in the oxide containing iron, ferrous salt or molysite
Or both more than composition be the iron black pigment being made of ferrous oxide and di-iron trioxide, wherein ferrous oxide and three aoxidize
The molar ratio of two iron is (0.2~0.8): (0.8~0.2)；Preferably, ferrous oxide and di-iron trioxide molar ratio are
0.33:0.67.
In some specific embodiments of the invention, the mass ratio of the folic acid and the iron oxide yellow is 1:(0.05
~20)；
The mass ratio of the folic acid and the ferrous succinate is 1:(0.05~20)；
The mass ratio of the folic acid and the ferrous fumarate is 1:(0.05~20)；
10 μm of partial size < of the oxide of the iron, the ferrous salt.
Based on the studies above, the present invention also provides the folate compositions to prepare answering in food and/or drug
With.
In addition, the present invention also provides food or health care product, including the composition or the folate composition with
And acceptable auxiliary material in food or health care product.
The present invention also provides drugs, containing acceptable in the composition or the folate composition and drug
Auxiliary material.
It needs to carry out double-dummy design in the clinical research of folic acid, in order to achieve the purpose that double blind, need in different size
Foliamin in appearance and size having the same.Folic acid itself is a kind of yellow, yellowish-brown or orange-yellow crystal powder
End at least needs the folic acid allotment of various dose becoming the same color, color and iron yellow in view of folic acid itself
It is similar, so the color of suitable iron oxide yellow pigment adjustment preparation is added in the folic acid specification of allotment various dose, due to worrying
The stability problem of folic acid in long-term clinical test has carried out stability tracking to deployed foliamin powder,
It is surprisingly found that the folic acid ingredient of iron oxide yellow is added, stability is very in long-term placement process in last tracking result
Outstanding, the degradation impurity A of folic acid does not change substantially, thus the present invention herein basis on carried out iron oxide yellow substance to folic acid
Stability influence research.Result of study shows, the ferrous succinate of folic acid and iron oxide yellow and brown color, the Asias such as ferrous fumarate
Molysite compatibility, can the conspicuousness raising folic acid stability wet to light.The product of folic acid and these molysite compatibilities can directly add
It is added in food additives, such as milk powder；It, can also be with other auxiliary materials together, such as starch, lactose etc. due to well-known
After mixing, pass through certain means tabletting, or filling capsule.
Specific embodiment
The invention discloses two in a kind of oxide of iron, ferrous salt or oxide, ferrous salt and molysite containing iron
Application of the composition in raising folic acid stability more than person or both, those skilled in the art can use for reference present disclosure,
It is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications carry out those skilled in the art
Say it is it will be apparent that they are considered as being included in the present invention.Method and application of the invention has passed through preferred embodiment
It is described, related personnel can obviously not depart from the content of present invention, in spirit and scope to method described herein and answer
With being modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
In previous application, iron-containing pigment is mainly used for food, health care product, and medicine field etc. adjusts articles color,
Improve article compliance.Iron-containing pigment and article are usually mixed together to the whole color sensation for being used to adjust article.And folic acid
This is as yellow crystalline powder, so unnecessarily using necessity of iron oxide yellow pigment when article containing folic acid.Therefore, the present invention is using often
The iron-containing yellow or brown color pigment seen improve folic acid to the stability of light.In the present invention, the iron-containing pigment (oxidation of iron
Composition more than the two in object, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both) include iron oxide yellow,
Mixture more than one or both of ferrous succinate or ferrous fumarate of brown color.
On this basis, the present invention also provides the oxide of iron, ferrous salt and/or oxide, ferrous salts containing iron
Or composition more than the two in molysite or both.The present invention also provides a kind of groups that folic acid and ferrous salt, molysite form
Object is closed, the oxide of iron is iron oxide yellow and/or di-iron trioxide, and ferrous salt mainly includes the ferrous succinate of brown color, palm fibre
The molysite product of the ferrous fumarate of yellow and other yellow or brown color.
After the present invention passes through iron-containing pigment, such as iron oxide yellow, and common brown iron dyestuff and folic acid are simply mixed, so that it may
This mixture is significantly improved to the stability of light.This mixture can be used for food, health care product, the fields such as pharmaceutical preparation.
Key point of the invention is can to greatly improve folic acid for adjusting the iron oxide yellow pigment of preparation color in general preparation
To the stability of light, after carrying out related work based on this, it is found to have the ferrous succinate of yellow or class yellow, rich horse
It is sour ferrous also with same function.
Partial size smaller iron oxide yellow pigment, ferrous succinate or ferrous fumarate, are more obvious the protective effect of light, for
Functionization considers that the present invention defines partial size less than 10 μm, preferably smaller than 5 μm, preferably less than 1 μm.
Two in the oxide of iron used in the present invention, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Preferred iron-containing pigment in composition more than person or both, more preferable yellow or brown color contain ferrichrome.Iron-containing pigment
(composition more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both)
There is this qualitative difference with pigment used in ordinary preparation, the oxide of iron provided by the invention, ferrous salt and/or contains iron
Composition more than the two in oxide, ferrous salt or molysite or both is mainly used for improving stability, and use ratio is
Folic acid: (group more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both
Close object)=1:(0.05~20), preferred 1:0.5~10.Specifically used amount is related to the partial size of the oxide of iron or ferrous salt, grain
Diameter is smaller, smaller using relative quantity, two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Total usage amount of composition more than person or both is less than the use standard volume (0~0.5mg/kg) of WHO, by calculating folic acid
Maximum odd-numbered day dosage, iron-containing yellow pigment (oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron
In the two or both more than composition) use total daily dose be smaller than 10mg.
Folate composition of the invention also has essential distinction with commercialized product ferrous fumarate and folic acid compound preparation.In rich horse
Folic acid dosage 0.35mg in the compound preparation of sour ferrous iron folic acid, ferrous fumarate dosage 322mg, the two mass ratio are 1:920 (w/
W), in the compound preparation of ferrous fumarate and folic acid, the partial size of ferrous fumarate does not make any control, and the rich horse in the present invention
Sour ferrous iron partial size is less than 10 μm.The average particle size range of iron-containing pigment is less than 10 μm, preferably smaller than 5 μm, preferably less than 1 μ
m。
For usage mode of the invention also different from the usage mode mixed colours in the past, the present invention is the iron content by folic acid and selection
Yellow pigment (the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both with
On composition) after mixing, then mix with other materials, finished product be made.Folic acid and the (oxidation of iron of iron content colorant composition
Composition more than the two in object, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both) preparation side
Method is taken containing ferrichrome (the two or two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Composition more than person) and folic acid be mixed directly under conditions of being protected from light to obtain the final product.Specifically, new group of the folic acid in the present invention
Closing object preparation method is by folic acid and iron-containing yellow pigment (oxide of iron, ferrous salt and/or the oxide containing iron, Asia
Composition more than the two in molysite or molysite or both) directly mix, mixing apparatus includes, but are not limited to high-efficiency wet legal system
Grain machine, high-speed mixer, disintegrating machine etc..
In the present invention, the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or
The folate composition that more than the two composition and folic acid are formed is a kind of Primary product, can be used for being further processed into market
Final product.It is more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both
Composition and the folate composition that is formed of folic acid can be used for multiple fields, such as food additives, the preparation of health care product contains folic acid
Pharmaceutical preparation etc., can greatly improve the photostability of folic acid.
The two in the oxide of iron provided by the invention, ferrous salt and/or oxide, ferrous salt or molysite containing iron
Or both more than composition improve folic acid stability in being available on the market using involved raw material and reagent,
Or it is obtained by prior art preparation.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1
Take folic acid 10g and iron oxide yellow 20g, 1 μm of iron oxide yellow average grain diameter, (d50=1.0 μm, d90=3 μm), in keeping away
Luminous environment is uniformly mixed, and obtains golden yellow folic acid new compositions.Folic acid iron oxide yellow composition 3g is taken simultaneously, then takes microcrystalline cellulose
282.5g, pregelatinized starch 12.5g, magnesium stearate 3g, mixing is uniform, adjusts slice weight 120mg, and tabletting obtains new group of 0.4mg
It closes object Couteat of Folic Acid (piece 1)；Same amount folic acid raw material 1g and microcrystalline cellulose 285.5g, pregelatinized starch 12.5, magnesium stearate are taken again
1g is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains common 0.4mg Couteat of Folic Acid (piece 2).Take folic acid iron oxide yellow composition, leaf
Acid starting material, piece 1, piece 2, acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively 0
It, 5 days, 10 days, samples, by British Pharmacopoeia, BP2013 method measures impurity A (N- (the 4- aminobenzoyl in sample for 30 days
Base)-Pidolidone), the results are shown in Table 1.The level of tablet made of new compositions and new compositions as seen from Table 1, impurity A is bright
It is aobvious to improve, and the tablet impurity that folic acid raw material is pressed into is already close to the upper limit (being not more than 1%) of Chinese Pharmacopoeia standard.
Embodiment 2
Take folic acid 10g and iron oxide yellow 200g, 10 μm of iron oxide yellow average grain diameter, (d50=10 μm, d90=15 μm), in
Light protected environment is uniformly mixed, and obtains golden yellow folic acid new compositions.Folic acid iron oxide yellow composition 21g is taken simultaneously, then takes crystallite fine
Element 263.5g, pregelatinized starch 12.5g, magnesium stearate 3g are tieed up, mixing is uniform, adjusts slice weight 120mg, and tabletting obtains 0.4mg's
New compositions Couteat of Folic Acid (piece 1)；Same amount folic acid raw material 1g and microcrystalline cellulose 283.5g are taken again, and pregelatinized starch 12.5 is stearic
Sour magnesium 3g is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains common 0.4mg Couteat of Folic Acid (piece 2).Folic acid iron oxide yellow is taken to combine
Object, folic acid raw material, piece 1, piece 2, acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, point
It not at 0 day, 5 days, 10 days, samples within 30 days, by British Pharmacopoeia, BP2013 method measures impurity A (N- (the 4- aminobenzene in sample
Formoxyl)-Pidolidone), the results are shown in Table 1.Tablet made of new compositions and new compositions as seen from Table 1, the water of impurity A
It is flat to be obviously improved, and the tablet impurity that folic acid raw material is pressed into is already close to the upper limit (being not more than 1%) of Chinese Pharmacopoeia standard.
Embodiment 3
Take folic acid 10g and iron oxide yellow 5g, 0.1 μm of iron oxide yellow average grain diameter, (d50=0.1 μm, d90=1 μm), in keeping away
Luminous environment strong mixing is uniformly mixed, and obtains golden yellow folic acid new compositions.Folic acid iron oxide yellow composition 1.5g is taken simultaneously, then takes crystallite fine
Element 283.0g, pregelatinized starch 12.5g, magnesium stearate 3g are tieed up, mixing is uniform, adjusts slice weight 120mg, and tabletting obtains 0.4mg's
New compositions Couteat of Folic Acid (piece 1)；Same amount folic acid raw material 1g and microcrystalline cellulose 283.5g are taken again, and pregelatinized starch 12.5 is stearic
Sour magnesium 3g is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains common 0.4mg Couteat of Folic Acid (piece 2).Folic acid iron oxide yellow is taken to combine
Object, folic acid raw material, piece 1, piece 2, acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, point
It not at 0 day, 5 days, 10 days, samples within 30 days, by British Pharmacopoeia, BP2013 method measures impurity A (N- (the 4- aminobenzene in sample
Formoxyl)-Pidolidone), the results are shown in Table 1.Tablet made of new compositions and new compositions as seen from Table 1, the water of impurity A
It is flat to be obviously improved, and the tablet impurity that folic acid raw material is pressed into is already close to the upper limit (being not more than 1%) of Chinese Pharmacopoeia standard.
Embodiment 4
Ferrous succinate is taken, being crushed to partial size with ball mill is 3~6 μm；Take folic acid raw material 10g, the succinic acid after smashing
Ferrous 50g is uniformly mixed, and obtains the new compositions of the folic acid of brown color；Folic acid new compositions 6g and starch 100g is taken to mix, then
Lactose 191g mixing is added, the appropriate wet granulation of 10% starch slurry is added, fluidized bed drying (controls temperature of charge less than 40 DEG C),
Magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains Couteat of Folic Acid of the 0.4mg containing new compositions
(piece 1)；It takes folic acid raw material 1g and starch 100g to mix, adds lactose 197g mixing, the appropriate wet process system of 10% starch slurry is added
Grain, fluidized bed drying (control temperature of charge is less than 40 DEG C), magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts slice weight
120mg, tabletting obtain the common Couteat of Folic Acid (piece 2) of 0.4mg.Take folic acid new compositions, folic acid raw material, piece 1, piece 2, respectively at
5000lux, 15~35 DEG C, acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, sample within 30 days,
1 method of embodiment measures the impurity A in sample, the results are shown in Table 1.
Seen from table 1, compared with raw material, folic acid new compositions tablet can be mentioned substantially the new compositions of folic acid compared with conventional tablet
Stability of the height to light.
Embodiment 5
Ferrous succinate is taken, being crushed to average grain diameter with ball mill is 0.5~1 μm；Folic acid raw material 10g is taken, after smashing
Ferrous succinate 5g is uniformly mixed, and obtains the new compositions of the folic acid of brown color；Take folic acid new compositions 1.5g and starch 100g
Mixing adds lactose 195.5g mixing, and the appropriate wet granulation of 10% starch slurry, fluidized bed drying (control temperature of charge is added
Less than 40 DEG C), magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains 0.4mg containing new compositions
Couteat of Folic Acid (piece 1)；It takes folic acid raw material 1g and starch 100g to mix, adds lactose 197g mixing, it is suitable that 10% starch slurry is added
Wet granulation is measured, fluidized bed drying (control temperature of charge is less than 40 DEG C), magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts
Slice weight 120mg, tabletting obtain the common Couteat of Folic Acid (piece 2) of 0.4mg.Take folic acid new compositions, folic acid raw material, piece 1, piece 2, difference
Acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5 days, 10 days, is taken within 30 days
Sample, 1 method of embodiment measure the impurity A in sample, the results are shown in Table 1.
Seen from table 1, compared with raw material, folic acid new compositions tablet can be mentioned substantially the new compositions of folic acid compared with conventional tablet
Stability of the height to light.
Embodiment 6
Ferrous succinate is taken, being crushed to average grain diameter with ball mill is 7.0~10.0 μm；Folic acid raw material 10g is taken, after smashing
Ferrous succinate 200g be uniformly mixed, obtain the new compositions of the folic acid of brown color；Take folic acid new compositions 21g and starch
100g mixing adds lactose 176g mixing, and the appropriate wet granulation of 10% starch slurry, fluidized bed drying (control material temperature is added
Degree is less than 40 DEG C), magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains 0.4mg containing Combination nova
The Couteat of Folic Acid (piece 1) of object；It takes folic acid raw material 1g and starch 100g to mix, adds lactose 197g mixing, 10% starch slurry is added
Appropriate wet granulation, fluidized bed drying (control temperature of charge is less than 40 DEG C), magnesium stearate 3g is added in whole grain, is uniformly mixed, and adjusts
Nodal plate weight 120mg, tabletting obtain the common Couteat of Folic Acid (piece 2) of 0.4mg.Take folic acid new compositions, folic acid raw material, piece 1, piece 2, point
Acceleration by light is tested not under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5 days, 10 days, is taken within 30 days
Sample, 1 method of embodiment measure the impurity A in sample, the results are shown in Table 1.
Seen from table 1, compared with raw material, folic acid new compositions tablet can be mentioned substantially the new compositions of folic acid compared with conventional tablet
Stability of the height to light.
Embodiment 7
Folic acid raw material 10g is taken, then taking average partial size is 0.3 μm of ferrous fumarate 5g, is uniformly mixed, is obtained brown with polishing
The folic acid new compositions of yellow；Folic acid new compositions 7.5g is taken, microcrystalline cellulose 101 .3g is taken, then takes low substituted hydroxy-propyl fiber
Magnesium stearate 1.2g is added in plain 10g, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains 5mg specification Couteat of Folic Acid (piece 1).Same method
Take 5g folic acid raw material, tabletting (piece 2).Take folic acid new compositions, folic acid raw material, piece 1, piece 2, respectively at 5000lux, 15~35
DEG C, acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, sample within 30 days, the measurement of 1 method of embodiment
Impurity A in sample, the results are shown in Table 1.
As seen from Table 1, compared with raw material, folic acid new compositions tablet can be mentioned substantially the new compositions of folic acid compared with conventional tablet
Stability of the height to light.
Embodiment 8
Folic acid raw material 10g is taken, then taking average partial size is 1 μm of ferrous fumarate 100g, is uniformly mixed, is obtained brown with polishing
The folic acid new compositions of yellow；Folic acid new compositions 11g is taken, takes microcrystalline cellulose 99g, then take low-substituted hydroxypropyl cellulose
Magnesium stearate 1.2g is added in 10g, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains 1mg specification Couteat of Folic Acid (piece 1).It is taken with method
1g folic acid raw material, tabletting (piece 2).Take folic acid new compositions, folic acid raw material, piece 1, piece 2, respectively at 5000lux, 15~35 DEG C,
Acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, is sampled within 30 days, 1 method of embodiment measures sample
Impurity A in product, the results are shown in Table 1.
As seen from Table 1, compared with raw material, folic acid new compositions tablet can be mentioned substantially the new compositions of folic acid compared with conventional tablet
Stability of the height to light.
Embodiment 9
Folic acid raw material 10g is taken, then taking average partial size is 9 μm of ferrous fumarate 200g, is uniformly mixed, is obtained brown with polishing
The folic acid new compositions of yellow；Folic acid new compositions 21g is taken, takes microcrystalline cellulose 261g, then take low-substituted hydroxypropyl cellulose
Magnesium stearate 3g is added in 15g, is uniformly mixed, and adjusts slice weight 120mg, and tabletting obtains 0.4mg specification Couteat of Folic Acid (piece 1).It is taken with method
1g folic acid raw material, tabletting (piece 2).Take folic acid new compositions, folic acid raw material, piece 1, piece 2, respectively at 5000lux, 15~35 DEG C,
Acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, is sampled within 30 days, 1 method of embodiment measures sample
Impurity A in product, the results are shown in Table 1.
As seen from Table 1, the new compositions of folic acid are compared with raw material, and folic acid new compositions tablet can be improved pair compared with conventional tablet
The stability of light.
Embodiment 10
Folic acid raw material 5g is taken, then taking average partial size is the iron oxide yellow 5g of 500nm, the two is uniformly mixed, and obtains new group of folic acid
Close object.Folic acid new compositions 2g, lactose monohydrate 56.8g, microcrystalline cellulose 50g, sodium carboxymethyl starch 10g, magnesium stearate 1.2g,
It is uniformly mixed, selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 1mg；Separately take folic acid raw material 1g, a water
Lactose 57.8g, microcrystalline cellulose 50g, sodium carboxymethyl starch 10g, magnesium stearate 1.2g are uniformly mixed, and select 4#Capsule charge,
Obtain the new compositions capsule (capsule 2) that specification is 1mg.Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell), and capsule 2 (is gone
Fall softgel shell), acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5 days,
It 10 days, samples within 30 days, 1 method of embodiment measures the impurity A in sample, the results are shown in Table 1.
As seen from Table 1, the new compositions of folic acid are filled compared with raw material, folic acid new compositions capsule filling compared with conventional capsule
Object can greatly improve the stability to light.
Embodiment 11
Folic acid raw material 10g is taken, then taking average partial size is the iron oxide yellow 5g of 500nm, the two is uniformly mixed, and obtains new group of folic acid
Close object.Folic acid new compositions 7.5g, lactose monohydrate 51.3g, microcrystalline cellulose 50g, sodium carboxymethyl starch 10g, magnesium stearate
1.2g is uniformly mixed, and selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 5mg；Folic acid raw material 5g separately is taken,
Lactose monohydrate 53.8g, microcrystalline cellulose 50g, sodium carboxymethyl starch 10g, magnesium stearate 1.2g are uniformly mixed, and select 4#Capsule
Filling obtains the new compositions capsule (capsule 2) that specification is 1mg.Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell),
Capsule 2 (removes softgel shell), and acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively 0
It, 5 days, 10 days, samples, 1 method of embodiment measures the impurity A in sample, the results are shown in Table 1 for 30 days.
As seen from Table 1, the new compositions of folic acid are filled compared with raw material, folic acid new compositions capsule filling compared with conventional capsule
Object can greatly improve the stability to light.
Embodiment 12
Folic acid raw material 5g is taken, then taking average partial size is the iron oxide yellow 100g of 500nm, the two is uniformly mixed, and obtains the new of folic acid
Composition.Folic acid new compositions 21g, lactose monohydrate 161g, microcrystalline cellulose 100g, sodium carboxymethyl starch 15g, magnesium stearate
3g is uniformly mixed, and selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 1mg；Separately take folic acid raw material 1g, one
Water and milk sugar 181g, microcrystalline cellulose 100g, sodium carboxymethyl starch 15g, magnesium stearate 3g are uniformly mixed, and select 4#Capsule charge,
Obtain the new compositions capsule (capsule 2) that specification is 0.4mg.Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell), capsule 2
(removing softgel shell), acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5
It 10 days, is sampled for 30 days, and 1 method of embodiment measures the impurity A in sample, the results are shown in Table 1.
As seen from Table 1, the new compositions of folic acid are filled compared with raw material, folic acid new compositions capsule filling compared with conventional capsule
Object can greatly improve the stability to light.
Embodiment 13
Folic acid raw material 5g is taken, then taking average partial size is 0.05 μm of medicinal iron oxide yellow 0.25g, the two is uniformly mixed, and obtains purple
The folic acid new compositions of color.Take folic acid the new compositions 1.05g, cornstarch 50g, lactose monohydrate 67.75g of purple, stearic acid
Magnesium 1.2g is uniformly mixed, and selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 1mg；Separately take folic acid raw material
1g, cornstarch 50g, lactose monohydrate 67.8g, magnesium stearate 1.2g are uniformly mixed, and select 4#Capsule charge, obtaining specification is
The new compositions capsule (capsule 2) of 1mg.Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell), and capsule 2 (removes softgel shell), point
Acceleration by light is tested not under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5 days, 10 days, is taken within 30 days
Sample, 1 method of embodiment measure the impurity A in sample, the results are shown in Table 1.
Embodiment 14
Folic acid raw material 10g is taken, then taking average partial size is 0.3 μm of medicinal iron oxide black 5g, the two is uniformly mixed, and obtains purple
Folic acid new compositions.Folic acid new compositions 7.5g, cornstarch 50g, lactose monohydrate 61.3g, the magnesium stearate 1.2g of purple are taken,
It is uniformly mixed, selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 5mg；Separately take folic acid raw material 5g, corn
Starch 50g, lactose monohydrate 63.8g, magnesium stearate 1.2g are uniformly mixed, and select 4#Capsule charge, obtaining specification is the new of 5mg
Composition capsule (capsule 2).Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell), and capsule 2 (removes softgel shell), respectively at
5000lux, 15~35 DEG C, acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, sample within 30 days,
1 method of embodiment measures the impurity A in sample, the results are shown in Table 1.
Embodiment 15
Folic acid raw material 5g is taken, then taking average partial size is 10 μm of medicinal iron oxide black 100g, the two is uniformly mixed, and obtains purple
Folic acid new compositions.Folic acid new compositions 21g, cornstarch 150g, lactose monohydrate 126g, the magnesium stearate 3.0g of purple are taken,
It is uniformly mixed, selects 4#Capsule charge obtains the new compositions capsule (capsule 1) that specification is 5mg；Separately take folic acid raw material 1g, corn
Starch 150g, lactose monohydrate 146.0g, magnesium stearate 3.0g are uniformly mixed, and select 4#Capsule charge, obtaining specification is 0.4mg
New compositions capsule (capsule 2).Folic acid new compositions, folic acid raw material are taken, capsule 1 (removes softgel shell), and capsule 2 (removes softgel shell), respectively
Acceleration by light is tested under conditions of 5000lux, 15~35 DEG C, humidity 40~65%, respectively at 0 day, 5 days, 10 days, is taken within 30 days
Sample, 1 method of embodiment measure the impurity A in sample, the results are shown in Table 1.
Embodiment 16
Take folic acid 10g, iron oxide yellow 33g, di-iron trioxide 67g, 1 μm of iron oxide yellow average grain diameter, (d50=1 μm, d90
=5 μm), 1 μm of di-iron trioxide average grain diameter, (d50=1 μm, d90=6 μm), it is uniformly mixed in light protected environment, obtains purple
Folic acid new compositions.Folic acid iron oxide yellow new compositions 11g is taken simultaneously, then takes microcrystalline cellulose 95.3g, pregelatinized starch 12.5g, firmly
Fatty acid magnesium 1.2g, mixing is uniform, adjusts slice weight 120mg, and tabletting obtains the new compositions Couteat of Folic Acid (piece 1) of 1mg；Same amount is taken again
Folic acid raw material 1g and microcrystalline cellulose 105.3g, pregelatinized starch 12.5, magnesium stearate 1.2g are uniformly mixed, and adjust slice weight
120mg, tabletting obtain common 1mg Couteat of Folic Acid (piece 2).Take folic acid iron oxide yellow composition, folic acid raw material, piece 1, piece 2, respectively at
5000lux, 15~35 DEG C, acceleration by light is tested under conditions of humidity 40~65%, respectively at 0 day, 5 days, 10 days, sample within 30 days,
By British Pharmacopoeia, BP2013 method measures the impurity A (N- (4- amino benzoyl)-Pidolidone) in sample, the results are shown in Table
1.Tablet made of new compositions and new compositions as seen from Table 1, the level of impurity A is obviously improved, and folic acid raw material is pressed into
Tablet impurity already close to Chinese Pharmacopoeia standard the upper limit (be not more than 1%).
Embodiment 17
Take folic acid 10g, iron oxide yellow 1g, di-iron trioxide 4g, 0.5 μm of iron oxide yellow average grain diameter, di-iron trioxide is flat
Equal 0.3 μm of partial size, is uniformly mixed in light protected environment, obtains purple folic acid new compositions.Folic acid new compositions 7.5g is taken simultaneously,
Microcrystalline cellulose 98.8g, pregelatinized starch 12.5g, magnesium stearate 1.2g are taken again, mixing is uniform, adjusting slice weight 120mg, tabletting,
Obtain the new compositions Couteat of Folic Acid (piece 1) of 5mg；Same amount folic acid raw material 5g and microcrystalline cellulose 106.3g, pregelatinized starch are taken again
12.5, magnesium stearate 1.2g are uniformly mixed, and adjust slice weight 120mg, and tabletting obtains common 5mg Couteat of Folic Acid (piece 2).Take folic acid
Iron oxide yellow composition, folic acid raw material, piece 1, piece 2, the acceleration by light under conditions of 5000lux, 15~35 DEG C, humidity 40~65%
Test samples for 30 days respectively at 0 day, 5 days, 10 days, and by British Pharmacopoeia, BP2013 method measures the impurity A (N- (4- in sample
Amino benzoyl)-Pidolidone), the results are shown in Table 1.Tablet made of new compositions and new compositions as seen from Table 1, it is miscellaneous
The level of matter A is obviously improved, and the tablet impurity that folic acid raw material is pressed into (is not more than already close to the upper limit of Chinese Pharmacopoeia standard
1%).
Embodiment 18
Take folic acid 10g, iron oxide yellow 160g, di-iron trioxide 40g, 10 μm of iron oxide yellow average grain diameter, di-iron trioxide
It 9 μm of average grain diameter, is uniformly mixed in light protected environment, obtains aubergine folic acid new compositions.The new iron oxide yellow combination of folic acid is taken simultaneously
Object 21g, then microcrystalline cellulose 261g is taken, pregelatinized starch 15g, magnesium stearate 3g mix uniform, adjusting slice weight 120mg, pressure
Piece obtains the new compositions Couteat of Folic Acid (piece 1) of 0.4mg；Same amount folic acid raw material 1g and microcrystalline cellulose 281.0g, pregelatinated are taken again
Starch 15g, magnesium stearate 3g are uniformly mixed, and adjust slice weight 120mg, and tabletting obtains common 0.4mg Couteat of Folic Acid (piece 2).It takes
Folic acid iron oxide yellow composition, folic acid raw material, piece 1, piece 2, the light under conditions of 5000lux, 15~35 DEG C, humidity 40~65%
Accelerated test samples for 30 days respectively at 0 day, 5 days, 10 days, and by British Pharmacopoeia, BP2013 method measures the impurity A in sample
(N- (4- amino benzoyl)-Pidolidone), the results are shown in Table 1.Piece made of new compositions and new compositions as seen from Table 1
The level of agent, impurity A is obviously improved, and the tablet impurity that folic acid raw material is pressed into already close to Chinese Pharmacopoeia standard the upper limit (no
Greater than 1%).
Embodiment 19
To product made from the embodiment of the present invention 1~18 respectively at 5000lux, 15~35 DEG C, the item of humidity 40~65%
Acceleration by light is tested under part, respectively at 0 day, 5 days, 10 days, is sampled within 30 days, by British Pharmacopoeia, BP2013 method is measured in sample
Impurity A (N- (4- amino benzoyl)-Pidolidone), the results are shown in Table 1.
1 sample impurity A of table
Note:#: p > 0.05
*: p < 0.05
**: p < 0.01.
As seen from the results in Table 1, for the new compositions of folic acid compared with raw material, the tablet of folic acid new compositions, capsule filling are more general
Logical tablet, capsule filling, can extremely significant (P < 0.01) improve the stability to light.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. group more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both
It closes object and is improving the application in folic acid stability；The oxide of the iron is the oxide of the iron of yellow or brown color；The Asia
Molysite is the ferrous salt of yellow or brown color.
2. group more than the two in the oxide of iron, ferrous salt and/or oxide, ferrous salt or molysite containing iron or both
Close application of the object in food of the preparation containing folic acid, health care product or drug；The oxide of the iron is yellow or brown color
The oxide of iron；The ferrous salt is the ferrous salt of yellow or brown color.
3. application as claimed in claim 1 or 2, which is characterized in that the oxide of the iron is iron oxide yellow and/or three oxidations
Two iron, the ferrous salt include the mixture of one or more of ferrous succinate or ferrous fumarate.
4. composition, which is characterized in that combination more than the two in oxide, ferrous salt including iron or molysite or both；
The oxide of the iron is the oxide of the iron of yellow or brown color；The ferrous salt is the ferrous salt of yellow or brown color.
5. composition as claimed in claim 4, which is characterized in that the oxide of the iron is iron oxide yellow and/or three oxidations
Two iron, the ferrous salt include two or more the mixture in ferrous succinate or ferrous fumarate.
6. folate composition, which is characterized in that it includes folic acid and composition as claimed in claim 5.
7. folate composition as claimed in claim 6, which is characterized in that the mass ratio of the folic acid and the iron oxide yellow is
1:(0.05~20)；
The mass ratio of the folic acid and the ferrous succinate is 1:(0.05~20)；
The mass ratio of the folic acid and the ferrous fumarate is 1:(0.05~20)；
10 μm of partial size < of the oxide of the iron, the ferrous salt.
8. folate composition as claimed in claims 6 or 7 is preparing the application in food and/or drug.
9. food or health care product, which is characterized in that including composition as claimed in claim 5 or as claimed in claims 6 or 7
Folate composition and food or health care product in acceptable auxiliary material.
10. drug, which is characterized in that folic acid containing composition as claimed in claim 5 or as claimed in claims 6 or 7
Acceptable auxiliary material in composition and drug.
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