CN104906067B - Ferrous composition of folic acid inclusion compound of a kind of stabilization and preparation method thereof and preparation - Google Patents
Ferrous composition of folic acid inclusion compound of a kind of stabilization and preparation method thereof and preparation Download PDFInfo
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Abstract
The invention discloses ferrous composition of folic acid inclusion compound of a kind of stabilization and preparation method thereof and preparation.The ferrous composition of the folic acid inclusion compound of described stabilization is made up of 30 ~ 40 parts of folic acid inclusion compounds of parts by weight, 50 ~ 500 parts of ferrous salts, 185 ~ 550 parts of auxiliary materials.Described preparation method includes pretreatment, preparation process.Described preparation adds pharmaceutically acceptable auxiliary material for the ferrous composition of the folic acid inclusion compound of described stabilization and is prepared into powder, tablet, capsule, granule.The present composition and technology of preparing can significantly improve the stability of existing folic acid and acid of ferrous salt pref middle period, be adapted to industrial-scale production and application.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the ferrous composition and its system of a kind of folic acid inclusion compound of stabilization
Preparation Method and preparation.
Background technology
Ferrous salt is the inorganic molysite for the treatment of hypoferric anemia, and ferrous fumarate has to be contained than traditional ferrous salt ferrous sulfate
Iron is high, gastric stimulation is small, proves effective the advantages that fast, is one of the key agents of China's treatment hypoferric anemia.Folic acid
（Folic Acid）, also referred to as vitamine M is a kind of water-soluble B vitamin, can cause during shortage megaloblastic anemia,
Neonate's NTD（NTDs）Deng.Although the country clinically has long been known that while supplements chalybeate and folic acid is pregnant to prevention
The importance of phase anaemia, but it is domestic at present still without fixed dosage of the exploitation containing two kinds of active ingredients of ferrous fumarate and folic acid
Compound preparation.And ferrous salt/folic acid compound preparation is in multinational list marketing abroad, wherein in the Pregaday of Britain's listing®Piece（304mg containing ferrous salt is equivalent to iron 100mg and the μ g of folic acid 350）, prevent iron and leaf after three weeks suitable for gestation most the tenth day of lunar month
Acid heat, turns into OTC medicines salable, and recorded by British Pharmacopoeia.
The poorly water-soluble of folic acid in the two kinds of active components of ferrous salt Couteat of Folic Acid, and to the factor such as light, heat, wet, oxygen not
It is stable, easily degraded during preparation processing and product preserve.Therefore it is to contain folic acid to improve its stability and water solubility
One of key issue of formulation application.Chinese patent literature disclose the B ferrous fumarate folic acid dispersible tablets of CN 10669954 and
Its preparation method, the U Ferrous Fumarate Compounds of CN 202568931 and folic acid Novel capsule and the A fumaric acid of CN 101632675
Ferrous three patents of folic acid pharmaceutical composition and its lipidosome solid preparation, the production technology personnel of this area should clearly recognize
Know, for industrialized production, first have to solve is the convenient, fast of production, medicine safely, effectively, stable and medicine
The controllable and relatively low cost of amount of substance.
But how research organically to be combined with production, produce the product of qualified stabilization, be still that researcher is careful
The careful problem treated and constantly brought forth new ideas.
The content of the invention
The first object of the present invention is a kind of ferrous composition for the folic acid inclusion compound for providing stabilization；Second purpose is
The preparation method of the ferrous composition of the folic acid inclusion compound of the stabilization is provided；3rd purpose is the folic acid for providing the stabilization
The preparation of the ferrous combination of inclusion compound.
The first object of the present invention is achieved in that the ferrous composition of the folic acid inclusion compound of described stabilization by weight
30 ~ 40 parts of folic acid inclusion compounds of part, 50 ~ 500 parts of ferrous salts, 185 ~ 550 parts of auxiliary materials compositions.
The second object of the present invention is achieved in that including pretreatment, preparation process, is specifically included：
A, pre-process：Raw material folic acid inclusion compound low-temperature grinding is crossed into 80 mesh sieves, ferrous salt crushed 100 mesh sieves, ingredient powder
The broken mesh sieve of mistake 80 is standby.
B, prepare：Supplementary material after pretreatment is uniformly mixed according to a ratio to obtain object.
The third object of the present invention is achieved in that the ferrous composition of the folic acid inclusion compound of described stabilization adds medicine
Acceptable auxiliary material is prepared into powder, tablet, capsule, granule on.
The present invention uses poloxamer F188It is polyoxyethylene polyoxypropylene block copolymer, is a kind of polyether-type nonionic
Type high molecular surfactant, poloxamer F188It is a kind of carrier of more satisfactory quick-acting solid dispersions, as nonionic
Type surfactant, the solubility of insoluble drug can be increased by forming micella, solid dispersion is prepared with fusion method, can
Greatly improve the dissolution rate and bioavilability of insoluble drug oral formulations；And there is relatively stable guarantor to carrier micelle agent
Shield acts on, therefore using poloxamer F188Inclusion is carried out to folic acid with preferable protectiveness and the dissolution rate of folic acid can be improved.
We employ direct powder compression technology in the production process of said preparation, and direct powder compression is that a kind of reduce is produced into
Originally the new pressed-disc technique of product quality, is improved, is a kind of simple, economic novel troche manufacture method, wet method system can be avoided
The damp and hot influence to active component stability during grain, content caused by because active component dosage is smaller can be overcome uneven
It is even.Invention significantly improves the stability of acid of ferrous salt pref middle period, and preparation method is simple, easy to operate, production cost
It is low, it is suitable for industrial-scale production.
Brief description of the drawings
Fig. 1 is preparation technology schematic flow sheet of the present invention.
Embodiment
The present invention is further illustrated below in conjunction with the accompanying drawings, but the present invention is not any limitation as in any way, base
In present invention teach that any conversion or replacement made, belong to protection scope of the present invention.
The ferrous composition of the folic acid inclusion compound of stabilization of the present invention by 30 ~ 40 parts of folic acid inclusion compounds of parts by weight, 50 ~
500 parts of ferrous salts, 185 ~ 550 parts of auxiliary material compositions.
Described auxiliary material by 50 ~ 150 parts of lactose of parts by weight, 100 ~ 300 parts of microcrystalline celluloses, 20 ~ 60 parts of PVPPs,
5 ~ 20 parts of PVPs, 5 ~ 10 parts of magnesium stearates, 5 ~ 10 parts of silica compositions.
Described folic acid inclusion compound is the inclusion compound of folic acid polyoxyethylene polyoxypropylene block copolymer.
The inclusion compound of the folic acid inclusion compound is polyoxyethylene polyoxypropylene block copolymer, mean molecule quantity is 7000 ~
9000。
The weight ratio of folic acid and polyoxyethylene polyoxypropylene block copolymer in described folic acid inclusion compound is 1：50~
200。
Described polyoxyethylene polyoxypropylene block copolymer is poloxamer F188。
Described ferrous salt be ferrous sulfate, ferrous fumarate, ferrous succinate, ferrous gluconate, iron-dextrin,
One or more in iron sucrose.
The preparation method of the ferrous composition of the folic acid inclusion compound of stabilization of the present invention, including pre-process, prepare step
Suddenly, specifically include：
A, pre-process：Raw material folic acid inclusion compound low-temperature grinding is crossed into 80 mesh sieves, ferrous salt crosses 100 mesh sieves, and auxiliary material crushed
80 mesh sieves are standby.
B, prepare：Supplementary material after pretreatment is uniformly mixed according to a ratio to obtain object.
The preparation of described raw material folic acid inclusion compound comprises the following steps：
A, polyoxyethylene polyoxypropylene block copolymer is melted in 40 ~ 60 DEG C of heating water baths；
B, folic acid is added by proportioning under the conditions of lucifuge, stirred, cooling and solidifying obtains object folic acid inclusion compound.
The preparation of the ferrous composition of the folic acid inclusion compound of stabilization of the present invention includes for the folic acid of described stabilization
The ferrous composition of thing adds pharmaceutically acceptable auxiliary material and is prepared into powder, tablet, capsule, granule.
It is an object of the invention to provide a kind of bag containing folic acid of the big production of suitable industrially scalable of quality controllable stabilization
Ferrous salt Couteat of Folic Acid of compound and preparation method thereof.
Folic acid inclusion compound of the present invention has following ratio, is shown in Table 1.
Placed 10 days under the conditions of above-mentioned inclusion compound is put into 40 DEG C of humidity 75% respectively, relevant material detected respectively at 0,10 day,
It the results are shown in Table 1.
The folic acid of table 1 and poloxamer F188Match influence factor table
First, 1 preparation method comprises the following steps in table 1：
1）Folic acid is crossed into 80 mesh sieves twice, it is standby to being uniformly dispersed.
2nd, 2 preparation method comprises the following steps in table 1：
1）By poloxamer F18880 mesh sieves are crossed after being mixed with folic acid twice, it is extremely well mixed, it is standby.
3rd, 3,4,5 preparation method comprises the following steps in table 1：
1）By poloxamer F188Melted in 40~60 DEG C of heating water baths.
2）Folic acid is slowly added under the conditions of lucifuge, stirring makes it well mixed, obtains the liquid of uniform yellow, cools down
Solidification.
3）Folic acid inclusion compound is crushed, crosses 80 mesh sieves, it is standby.
Conclusion：From the point of view of the data of 3,4,5 inclusions, relevant material is in acceptability limit.1st, the 2 folic acid raw materials not included are relevant
Material increases quickly, not in acceptability limit.
From production and folic acid stability angle, folic acid and poloxamer F188Proportioning preferably 1：100.
Ferrous salt Couteat of Folic Acid of the present invention is made up of the component of following parts by weight：30~40 parts of folic acid inclusion compound, ferrous salt n parts
（N is equivalent to iron content 100mg, such as 304 parts of ferrous fumarate）, 50~50 parts of lactose, 100~300 parts of microcrystalline cellulose, crosslinking it is poly-
Tie up 20~60 parts of ketone, 5~20 parts of PVP, 5~10 parts of magnesium stearate, 5~10 parts of silica.
It is preferred that：35.35 parts of folic acid inclusion compound, 304 parts of ferrous fumarate, 150 parts of lactose, 200 parts of microcrystalline cellulose, crosslinking
30 parts of PVP, 8 parts of PVP, 5 parts of magnesium stearate, 5 parts of silica.
I.e. preferably every 1000 folic acid inclusion compounds 35.35 g, ferrous fumarate 304g, lactose 150g, microcrystalline cellulose
200g, PVPP 30g, PVP 8g, magnesium stearate 5g, silica 5g.The present invention preparation process thereof include with
Lower step：
1）Pretreatment：Ferrous fumarate is crossed into 100 mesh sieves, folic acid inclusion compound crosses 80 mesh sieves, lactose crosses 40 mesh sieves, and crystallite is fine
Tie up element, PVPP, 30 POVIDONE K 30 BP/USP30, silica, magnesium stearate cross 80 mesh sieves, it is standby.
2）By poloxamer F188Melted in 40~60 DEG C of heating water baths.Folic acid is slowly added under the conditions of lucifuge, is stirred
Make it well mixed, obtain the liquid of uniform yellow, cool and solidify, low-temperature grinding, cross 80 mesh sieves, it is standby.
3）The mixing of supplementary material：The microcrystalline cellulose of recipe quantity is sequentially added in the folic acid inclusion compound of prepared recipe quantity
Element, lactose, PVPP, 30 POVIDONE K 30 BP/USP30, it is well mixed, adds recipe quantity ferrous fumarate, is well mixed, is eventually adding
Recipe quantity silica, magnesium stearate, it is well mixed.
3）Tabletting is produced using direct powder compression technology, coating.
By the same technique ferrous fumarate and folic acid piece of the amount of above-mentioned prescription 10000 using listing dummy packages（It is double
Aluminium）, strong light is put respectively（4500lx）, high humidity（RH92.5%）, high temperature（60℃）Under the conditions of 10 days, respectively at 0,5,10 day detect
Indices.Placed 10 days under the conditions of each, compared with 0 day, in addition to relevant material is increased slightly, remaining every quality index is without bright
Aobvious change.
（One）, enlarged experiment production carried out according to above-mentioned prescription, technique, obtain three batches of enlarged experiment samples, be respectively
1-1,1-2,1-3, and detected.It the results are shown in Table 2, table 3.
2 three batches of enlarged experiment creation datas of table
3 three batches of enlarged experiment quality summarized results of table
（Two）, Acceleration study：By three batches of samples（Lot number is：1-1、1-2、1-3）And embodiment 1 is packed using double aluminium,
40 DEG C, RH75% constant temperature, place 6 months in constant humidity cabinet, sampled respectively at 0,1,2,3,6 month, determine every quality index,
It the results are shown in Table 4.
As a result show：After test agent is using double aluminium packagings in three batches, 6 are placed under the conditions of 40 DEG C, RH75% accelerated test
Individual month, every quality index had no significant change compared with 0 month, met the pertinent regulations in quality standard.Embodiment 1, leaf
The relevant material of acid was rised appreciably after 1 month, and the pertinent regulations in quality standard are not met after 2 months.
（Three）, long term test：By test agent in three batches（Lot number is：1-1、1-2、1-3）And embodiment 1 is using double aluminium bags
Dress, it is placed in 25 DEG C, under the conditions of RH60%, was sampled respectively at 0,3,6,9,12,18 month, detect every quality index, the results are shown in Table
5。
As a result show：After test agent is using double aluminium packagings in three batches, placed under the conditions of 25 DEG C, RH60% long term test
24 months, every quality index had no significant change compared with 0 month, met the pertinent regulations in quality standard.The leaf of embodiment 1
The relevant material of acid rised appreciably after 3 months, did not met the pertinent regulations in quality standard.
Conclusion：The reappearance of this prescription is preferable, workable, quality controllable, is adapted to industrialized production.It is thus determined that
Prescription is every 1000 folic acid inclusion compounds 35.35g, ferrous fumarate 304g, lactose 150g, microcrystalline cellulose 200g, crosslinking are poly-
Tie up ketone 30g, PVP 8g, magnesium stearate 5g, silica 5g.
Preparation technology：
1）Pretreatment：Ferrous fumarate is crossed into 100 mesh sieves, folic acid inclusion compound crosses 80 mesh sieves, lactose crosses 40 mesh sieves, and crystallite is fine
Dimension element, PVPP, PVP K30, silica, magnesium stearate cross 80 mesh sieves, standby.
2）Poloxamer F188 is melted in 40~60 DEG C of heating water baths.Folic acid is slowly added under the conditions of lucifuge, is stirred
Make it well mixed, obtain the liquid of uniform yellow, cool and solidify, crush, cross 80 mesh sieves, it is standby.
3）The mixing of supplementary material：The microcrystalline cellulose of recipe quantity is sequentially added in the folic acid inclusion compound of prepared recipe quantity
Element, lactose, PVPP, PVP K30, it is well mixed, adds recipe quantity ferrous fumarate, be well mixed, finally adds
Enter recipe quantity silica, magnesium stearate, be well mixed.
4）Tabletting is produced using direct powder compression technology, coating.
The solid pharmaceutical preparation of the ferrous salt Couteat of Folic Acid of the inclusion compound provided by the invention containing folic acid, mainly has the advantage that：
1）Folic acid is included by poloxamer F188, solves the problems, such as folic acid stability difference, and solve folic acid and ferrous iron
The mixing that differs greatly of salt ratio is difficult to the problem of uniform, improves the drug effect and bioavilability of folic acid, ensure that the quality of product.
2）Using direct powder compression technology, reduce production cost, improve product quality, be a kind of simple, economical
Novel troche manufacture method, the damp and hot influence to active component stability in wet-granulation process can be avoided, and can overcome due to
Content caused by active component dosage is smaller is uneven.
3）This formulation and technology is stable, and favorable reproducibility is workable, quality controllable, is adapted to the big production of industrially scalable.
The ferrous fumarate and folic acid piece Core formulation of embodiment 1 screens（20000 dosages）
Preparation method：Folic acid and poloxamer F188 are weighed, is well mixed with equivalent principle of progressively increasing, obtains folic acid female powder, mistake
80 mesh sieves are standby.It is female to weigh recipe quantity ferrous fumarate, lactose, PVPP, PVP K30, microcrystalline cellulose and folic acid
Powder, it is well mixed, adds recipe quantity silica, magnesium stearate, be well mixed, determines angle of repose, tabletting.
Conclusion：Angle of repose is 29.7, and compressibility is good, friability 0.1%.
The ferrous fumarate and folic acid tablet recipe label of embodiment 2 screens（20000 dosages）
Preparation method：By recipe quantity poloxamer F188 40~60 DEG CHeating melting, adds recipe quantity folic acid, makes under agitation
It is well mixed, is cooled to room temperature, crushes, and crosses 80 mesh sieves, sequentially add recipe quantity microcrystalline cellulose, lactose, PVPP,
PVP K30, it is well mixed, adds recipe quantity ferrous fumarate, be well mixed, is eventually adding recipe quantity silica, hard
Fatty acid magnesium, it is well mixed.Determine angle of repose, tabletting.
Conclusion：Angle of repose is 27.8, and compressibility is good, friability 0.08%.
Embodiment 1 and embodiment 2 are pressed plain piece to be coated by embodiment 3, determine dissolution rate.
（1）Ferrous fumarate dissolution determination：This product is taken, according to dissolution method（Chinese Pharmacopoeia version two in 2010 is attached
Record X the second methods of C）, using 0.1mol/L hydrochloric acid 900ml as dissolution medium, regulation rotating speed is 75 turns per minute, is taken at 45 minutes
Sample filters, and takes subsequent filtrate 100ml, adds Phen indicator 2 and drips, uses ceriometry liquid rapidly（0.01mol/L）Titration,
And result is corrected with blank test.Per 1ml ceriometry liquid（0.01mol/L）Equivalent to 1.699mg ferrous salts.As a result see
Table 6.
（2）Folic acid dissolution determination：
This product is taken, according to dissolution method（Chinese Pharmacopoeia two annex X the second methods of C of version in 2010）, with phosphate-buffered
Liquid（pH6.8）900ml is dissolution medium, and regulation rotating speed is 75 turns per minute, was sampled at 45 minutes in right amount, filtration, takes continuous filter
Liquid, as need testing solution.It is appropriate that another precision weighs folic acid reference substance, is dissolved with 0.57% dipotassium hydrogen phosphate solution, and use dissolution
The solution of the μ g/ml containing folic acid 0.4 is made in medium, as reference substance solution.Reference substance solution and sample solution 200 are taken respectively
μ l inject liquid chromatograph, by external standard method with every stripping quantity of calculated by peak area.It the results are shown in Table 6.
The dissolution determination result of table 6
It is equal from dissolution determination result, the tablet ferrous fumarate made with embodiment 2 of embodiment 1, folic acid dissolution rate
It is higher, therefore select embodiment 1 to be placed 10 days under the conditions of 40 DEG C of humidity 75% with 2 made tablet of embodiment, it the results are shown in Table 7.
The prescription screening influence factor of table 7 is tested
| Embodiment | 0 day relevant material | 10 days relevant materials |
| 1 | 3.76% | 9.82% |
| 2 | 3.63% | 3.87% |
From above testing result：2 made tablet stability of embodiment is preferable.Folic acid is through poloxamer in the formulation
F188Stability after inclusion, which is better than, passes through poloxamer F188The folic acid of inclusion.
The ferrous sulfate folic acid tablet recipe label of embodiment 4 screens（20000 dosages）
Preparation method：By 40~60 DEG C of heating meltings of recipe quantity poloxamer F188, recipe quantity leaf is added under agitation
Acid, make it well mixed, be cooled to room temperature, crush, cross 80 mesh sieves, sequentially add recipe quantity microcrystalline cellulose, lactose, be crosslinked and gather
Tie up ketone, PVP K30, be well mixed, add recipe quantity ferrous sulfate, be well mixed, be eventually adding recipe quantity silica,
Magnesium stearate, it is well mixed.Tabletting.
Conclusion：Compressibility is good, the % of folate content 97.5, ferrous sulfate content 99.8%.
The ferrous fumarate and folic acid tablet recipe label of embodiment 5 screens（20000 dosages）
Preparation method：By 40~60 DEG C of heating meltings of recipe quantity poloxamer F188, recipe quantity leaf is added under agitation
Acid, make it well mixed, be cooled to room temperature, crush, cross 80 mesh sieves, sequentially add recipe quantity microcrystalline cellulose, lactose, be crosslinked and gather
Ketone, PVP K30 are tieed up, is well mixed, adds recipe quantity ferrous salt, is well mixed, is eventually adding recipe quantity silica, hard
Fatty acid magnesium, it is well mixed.Tabletting.
Conclusion：Compressibility is good, the % of folate content 99.4, ferrous salt content 98.9%.
The ferrous fumarate and folic acid piece Bioequivalence of embodiment 6 is tested
28 health volunteers intersect 2, oral test preparation at random（0.7mg containing folic acid, ferrous fumarate 608mg）With
Reference preparation 5（Couteat of Folic Acid 2,0.8mg containing folic acid；Ferrous fumarate piece 3,600mg containing ferrous fumarate；Two medicines are simultaneously
Take）, with the concentration of ferrous fumarate in aas determination blood plasma, folic acid and 5- in blood plasma are determined with HPLC-MS/MS methods
Methyl tetrahydrofolate concentration.
（1）Ferrous fumarate
After 28 health volunteer's oral test preparations, the relative bioavailability with area-method estimation by test preparation, by
The relative bioavailability of test preparation is（107.4%±20.5%）；Estimate ferrous fumarate TmaxAnd CmaxRespectively（4.607±
0.284）H and（1.958±0.181）Mg/mL, AUC0-12For（9.9±1.421）mg/mL*h.After oral reference preparation, estimation
Ferrous fumarate TmaxAnd CmaxRespectively（4.607±0.315）H and（1.838±0.178）Mg/mL, AUC0-12For（9.374±
1.329）mg/mL*h.
To the pharmacokinetic parameters C by test preparation and reference preparationmax、AUC0-12、AUC0-¥Variance is carried out after Logarithm conversion
Analysis, and further carry out evaluation of bioequivalence, wherein T using two one-sided t tests and 90% confidential interval methodmaxUsing non-
Parametric method（Wilcoxon signed rank tests）Examine.As a result show：Cmax、AUC0-12、AUC0-¥Refuse biological inequivalence to assume.
To by test preparation, the C after Logarithm conversionmax、AUC0-12、AUC0-¥90% confidential interval be respectively 101.8%~111.6%,
99.3%~112.3%, 103.3%~120.3%, with reference preparation TmaxDifference through nonparametric method examine it is not statistically significant（P>
0.05）.
（2）Folic acid
① FA
Complete 28 oral reference preparations of subject of experiment（0.8mg containing folic acid）With by test preparation（0.7mg containing folic acid）
Estimate FA CmaxRespectively（21.55±8.57）Nmol/L and（17.07±9.85）Nmol/L, TmaxRespectively（1.99±
1.45）H and（1.92±1.18）h.CmaxVariance analysis is first carried out after Logarithm conversion, then carries out Doubled haploid population.Dose modification
Afterwards, Doubled haploid population result shows, parameter CmaxBioequivalence, 90% confidential interval are 87.27% ~ 127.39%.TmaxThrough non-
Parametric method examines no significant difference (P>0.05).Although FA is endogenous, food-borne material, but sheet before its medication
Bottom concentration is less than test limit, and rapid conversion in vivo, except CmaxAnd its neighbouring several concentration points, remaining is below detecting
Limit, therefore the △ AUC of FA AUC, the deduction background and △ C for deducting backgroundmaxCalculated etc. equivalence is not involved in.
2. FA and 5-MTFA total mole number
Complete 28 oral reference preparations of subject of experiment（0.8mg containing folic acid）With by test preparation（0.7mg containing folic acid）,
Estimate FA and 5-MTFA total mole number CmaxRespectively（96.31±29.23）Nmol/L and（90.39±25.87）Nmol/L,
Obtained AUC is estimated with trapezoidal faces area method0-12Respectively（766.97±254.56）Nmol/L*h and（725.03±231.01）
nmol/L*h。AUC0-12、CmaxVariance analysis is first carried out after Logarithm conversion, then carries out Doubled haploid population.After dose modification, double lists
Side t assays show, two parameter CmaxAnd AUC0-12Bioequivalence, 90% confidential interval are respectively 97.63%~117.77% He
97.52%~119.24%.
28 oral reference preparations of subject（0.8mg containing folic acid）With by test preparation（0.7mg containing folic acid）Before in blood plasma
5-MTFA has certain background concentration（C0）Respectively 45.97 ± 48.8nmol/L and 41.73 ± 19.45nmol/L, then △ Cmax
Respectively 50.34 ± 16.43nmol/L and 48.60 ± 14.40nmol/L, obtained △ AUC are estimated with trapezoidal faces area method0-12Point
Wei not 215.31 ± 121.68nmol/L*h and 224.25 ± 96.77nmol/L*h.△AUC0-12、△CmaxAfter Logarithm conversion first
Variance analysis is carried out, then carries out Doubled haploid population.After dose modification, Doubled haploid population result shows, parameter △ CmaxBiology etc.
Effect, 90% confidential interval are 97.92% ~ 127.22%；Parameter △ AUC0-12Non- bad effect, 90% confidential interval be 92.34%~
215.18%。
Result above shows that the ferrous fumarate and folic acid piece (by test preparation) and Jiangxi pharmacy Limited Liability that we produce are public
Take charge of the ferrous fumarate piece developed（Reference preparation）With bioequivalence；The folic acid produced with Beijing Beida Pharmaceutical Industry Co., Ltd.
Piece（Reference preparation）Not deducting background has bioequivalence, deducts parameter △ C after backgroundmaxBioequivalence, parameter △ AUC0-12
Non- bad effect.
Claims (5)
- A kind of 1. ferrous composition of the folic acid inclusion compound of stabilization, it is characterised in that the ferrous iron of the folic acid inclusion compound of described stabilization Composition is made up of 30 ~ 40 parts of folic acid inclusion compounds of parts by weight, 50 ~ 500 parts of ferrous salts, 185 ~ 550 parts of auxiliary materials；The auxiliary material is by weight Measure part 50 ~ 150 parts of lactose, 100 ~ 300 parts of microcrystalline celluloses, 20 ~ 60 parts of PVPPs, 5 ~ 20 parts of PVPs, 5 ~ 10 parts it is hard Fatty acid magnesium, 5 ~ 10 parts of silica compositions；The preparation of the folic acid inclusion compound comprises the following steps：A, by poloxamer F188Melted in 40 ~ 60 DEG C of heating water baths；B, folic acid is added by proportioning under the conditions of lucifuge, stirred, cooling and solidifying obtains folic acid inclusion compound.
- 2. the ferrous composition for the folic acid inclusion compound stablized according to claim 1, it is characterised in that the folic acid inclusion compound Middle folic acid and F188Weight ratio be 1:50~200.
- 3. the ferrous composition for the folic acid inclusion compound stablized according to claim 1, it is characterised in that the ferrous salt is sulphur One or more in sour ferrous iron, ferrous fumarate, ferrous succinate, ferrous gluconate, iron-dextrin, iron sucrose.
- 4. a kind of preparation method of the ferrous composition of the folic acid inclusion compound of any stabilization of claim 1 ~ 3, its feature exist In including pretreatment, preparation process, specifically include：A, pre-process：Raw material folic acid inclusion compound low-temperature grinding is crossed into 80 mesh sieves, ferrous salt crushed 100 mesh sieves, and auxiliary material crushed 80 mesh sieves are standby；B, prepare：Supplementary material after pretreatment is uniformly mixed according to a ratio to obtain object.
- A kind of 5. preparation of the ferrous composition of the folic acid inclusion compound of any stabilization of claim 1 ~ 3, it is characterised in that institute The ferrous composition of the folic acid inclusion compound for the stabilization stated prepares piece agent.
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| CN107279988A (en) * | 2017-05-16 | 2017-10-24 | 柳州联云科技有限公司 | One kind is enriched blood food and preparation method thereof |
| CN109701027A (en) * | 2019-01-24 | 2019-05-03 | 北京斯利安药业有限公司 | A kind of folic acid pharmaceutical composition and folic acid pharmaceutical preparation of novel enhancing folic acid antioxidant |
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