CN105395554B - A kind of folic acid solid dispersions and preparation method thereof - Google Patents
A kind of folic acid solid dispersions and preparation method thereof Download PDFInfo
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- CN105395554B CN105395554B CN201410465045.6A CN201410465045A CN105395554B CN 105395554 B CN105395554 B CN 105395554B CN 201410465045 A CN201410465045 A CN 201410465045A CN 105395554 B CN105395554 B CN 105395554B
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- folic acid
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- hydrophilic carrier
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- acid solid
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 347
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 181
- 239000011724 folic acid Substances 0.000 title claims abstract description 179
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims abstract description 169
- 229960000304 folic acid Drugs 0.000 title claims abstract description 169
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 54
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 239000012052 hydrophilic carrier Substances 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 28
- 238000009472 formulation Methods 0.000 claims abstract description 21
- 229920001983 poloxamer Polymers 0.000 claims abstract description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 5
- 229930195725 Mannitol Natural products 0.000 claims abstract description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000594 mannitol Substances 0.000 claims abstract description 5
- 235000010355 mannitol Nutrition 0.000 claims abstract description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 3
- 238000009826 distribution Methods 0.000 claims abstract description 3
- 229960000502 poloxamer Drugs 0.000 claims abstract description 3
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 3
- 229940069328 povidone Drugs 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims description 45
- 238000002844 melting Methods 0.000 claims description 16
- 230000008018 melting Effects 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 230000008014 freezing Effects 0.000 claims description 8
- 238000007710 freezing Methods 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- 229960003511 macrogol Drugs 0.000 claims description 7
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 3
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- 230000000052 comparative effect Effects 0.000 description 49
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- 238000012360 testing method Methods 0.000 description 21
- 238000000034 method Methods 0.000 description 18
- JOAQINSXLLMRCV-UHFFFAOYSA-N 4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}benzoic acid Chemical compound C1=NC2=NC(N)=NC(O)=C2N=C1CNC1=CC=C(C(O)=O)C=C1 JOAQINSXLLMRCV-UHFFFAOYSA-N 0.000 description 17
- 239000000126 substance Substances 0.000 description 13
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 12
- 229920002472 Starch Polymers 0.000 description 12
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 150000002224 folic acids Chemical class 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 2
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 2
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
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- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
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- 230000003190 augmentative effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
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- 125000001747 pteroyl group Chemical group [H]C1=C([H])C(C(=O)[*])=C([H])C([H])=C1N([H])C([H])([H])C1=C([H])N=C2N([H])C(N([H])[H])=NC(=O)C2=N1 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to medicine fields, more particularly to a kind of folic acid solid dispersions and preparation method thereof, the solid dispersions include folic acid and hydrophilic carrier, the weight ratio of the folic acid and hydrophilic carrier is 1: 5-1: 50, and the hydrophilic carrier is one of poloxamer, polyethylene glycol, povidone, mannitol or more than one compositions；The size distribution of folic acid solid dispersions of the present invention is in the range of 80~150 mesh, the preparation method of the solid dispersions is fusion method or polishing, the clinical preparation form of the solid dispersions is oral solid formulation, and 30 minutes dissolution rates of oral solid formulation are not less than 90%；Folic acid solid dispersions of the present invention have content is uniform, dissolution rate is good, bioavilability is high, stability is good comprehensive advantage, also have the characteristics that it is environmental-friendly, be easy to realization of industrialization.
Description
Technical field
The present invention relates to belong to pharmaceutical technology field more particularly to a kind of folic acid solid dispersions and preparation method thereof.
Background technique
Folic acid (Folic Acid) belongs to B family vitamin, also known as vitamine M, folic acid, Vitamin B9, and chemistry is entitled
N- [4- [(2- amino -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridine) methylamino] benzoyl]-Pidolidone, commonly referred to as pteroyl paddy ammonia
Acid, molecular formula C19H19N7O8(the structural formula such as following figure), molecular weight 441.4,250 DEG C of fusing point, being practically insoluble in water, (solubility is about
For 0.0016mg/mL) and most of organic solvents, diluted acid and alkaline solution can be dissolved in.
For a long time, Yang Yuzhu, Crown Prince's inflammation etc. are general in " progress of folic acid " text for the clinical application historical origin of folic acid
Stated it and found applicating history: early in 1931, doctor Lucy doctor Wills of Bombay,India maternity hospital was had found, yeast
Or liver extract can improve the megaloblastic anemia of women, therefore, it is considered that in these extracts containing certain anti-anemia action because
Son；Nineteen thirty-five, someone have found the factor of anti-monkey anaemia in yeast and liver concentrate；Nineteen thirty-nine, someone sent out in liver again
The factor of anti-chicken anaemia is showed；Nineteen forty-one, American scholar Mitchell et al. have found one of streptococcus lactis in spinach
Growth factor because being mainly derived from leaves of plants, therefore is named as folic acid；1945, Angier et al. was in synthesis pteroylglutamic acid
Shi Faxian, above-mentioned discovery are same substance, have been completed at the same time the measurement of folic acid structure.
With the development of clinical medicine and modern science, folic acid obtains more deeply being widely applied in clinical practice,
Especially prevention newborn's neural tube malformation, megaloblastic anemia prevention and treatment in terms of embody exact curative effect with it is excellent
Gesture produces positive clinical effectiveness and extensive social benefit；Meanwhile modern medical science is research shows that folic acid is reducing height
Also there is good effect, homocysteine is usually defined as cardiovascular and cerebrovascular disease by medical field in terms of homocysteine
Independent risk factor, therefore, more and more researchs focus on folic acid in the application in cardiovascular and cerebrovascular disease field, have accumulated
Evidence show folic acid in terms of cardiovascular and cerebrovascular disease have exciting prospect；Currently, the potential medical value of folic acid is also
It is found to realize constantly, such as it also embodies certain clinical effect in anti-oxidant, anti-tumor aspect.
The immense value of folic acid clinic is undeniable and queries, it is well known, however, that a clinical drug was worth
Embodying has great relationship with physicochemical property, biological property and the clinical preparation form of active constituent.For folic acid,
Its physical and chemical feature for being insoluble in water and most organic solvents, brings difficulty to its dissolution in vitro, vivo biodistribution availability
With the obstacle gone beyond, giving full play to for its clinical value is ultimately limited, therefore, improves and solves folic acid and take orally vivo biodistribution benefit
The low problem of expenditure is very necessary as pharmaceutical technology field and has the work of huge meaning.
Currently, the main form of medication of folic acid clinically is normal oral solid tablet, in the prior art Beijing Huaan Buddhist
Medical research centered finite company application " folic acid dropping pill and preparation method thereof " (application number: 200610099026.1), Guangdong
" a kind of folic acid effervescent tablet and preparation method thereof " (application number: 200710107195.X) of Shi Xin pharmaceutcal corporation, Ltd application, day
The application of Fleder medical sci-tech Development Co., Ltd, Jinshi City " a kind of folic acid pellet and preparation method thereof " (application number:
200810182808.0) it is all made of new preparation technique, to improve the dissolution in vitro situation of folic acid, but, it is not sent out through analyzing
The existing technology has the compelling evidence and beneficial effect for improving folic acid oral administration biaavailability.
In summary, there is no effective technological means at present is clinically to provide a kind of folic acid drug of more advantage, because
This, it is currently a kind of with content is uniform, dissolution rate is good, bioavilability is high, the good comprehensive advantage of stability there is an urgent need to provide
Clinical medicine.
Summary of the invention
To solve the above-mentioned problems, the purpose of the present invention is to provide a kind of folic acid solid dispersions and preparation method thereof.
This folic acid solid dispersions one kind is with content is uniform, dissolution rate is high, bioavilability is high and stability is good
Good characteristic.
In order to solve the above technical problems, the present invention uses following technical scheme, a kind of folic acid solid dispersions include folic acid
And hydrophilic carrier, the weight ratio of the folic acid and hydrophilic carrier are 1: 5~1: 50.
Preferably, the weight ratio of the folic acid and hydrophilic carrier is 1: 10~1: 30, further preferably 1: 15.
The hydrophilic carrier is one of poloxamer, polyethylene glycol, povidone, mannitol or more than one combinations
Object.
Preferably, the hydrophilic carrier is one of PLURONICS F87, Macrogol 4000, Macrogol 6000
Or more than one compositions.
The size distribution of the folic acid solid dispersions is within the scope of 80~150 mesh.
The dosage form of the folic acid solid dispersions clinically is oral solid formulation.
0.2~10.0mg containing folic acid, preferably 0.4~5.0mg in the oral solid formulation unit formulation.
The oral solid formulation includes the pharmaceutically acceptable excipient for preparations shaping.
30 minutes dissolution rates of oral solid formulation are not less than 90%.
The oral solid formulation is not limited to tablet, capsule, granule, powder.
The preparation method of the folic acid solid dispersions is fusion method or polishing.
Preferably, the preparation method is that fusion method, includes the following steps:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, is first melted carrier completely under the conditions of 65~80 DEG C, then
Folic acid, stirring to complete melting is added；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 4~12 hours under the conditions of -15~-30 DEG C；
3) 2 after taking freezing) resulting material takes out after 2~6 hours dry under the conditions of 35~45 DEG C, crushes and sieve
Material within the scope of 80~150 mesh is to get folic acid solid dispersions.
The folic acid solid dispersions of the present invention obtained by adopting the above technical scheme, can preferably generate institute of the present invention
Purpose and technical effect to be achieved, specifically, a kind of folic acid solid dispersions of the present invention and preparation method thereof can
Generate: 1) uniformity of dosage units is high；2) dissolved corrosion is good, and vivo biodistribution availability is high；3) the Advantageous effect having good stability
Fruit.Further, a kind of folic acid solid dispersions of the present invention and preparation method thereof, also have it is environmental-friendly, be easy to industrialize
Amplify implementation trade-off advantage.
It should be noted that here, in order to enable the more clear errorless understanding of technical field personnel of the present invention
Summary of the invention and technical connotation of the invention, the present inventor are applied to the technical term being related to, symbol
Reagent consumptive material and instrument and equipment do as described below:
" mesh ": refer to the granularity measurement unit stated in Chinese Pharmacopoeia 2010 editions；
" instrument and equipment ": no special instruction is commercially available routine instrument device；
" auxiliary material reagent ": no special instruction is commercially available conventional reagent consumptive material；
" Tmax ": time when drug after medicine reaches maximum plasma concentration is showed；
" Cmax ": the maximum plasma concentration detected after medicine in body is showed；
" unit formulation ": referring to the per unit preparation of the folic acid oral solid formulation, such as refer to 1 for tablet,
Capsule refers to 1, and granule, powder refer to 1 bag；
“AUC0~∞": refer to lower area of blood concentration-time curve, during bioavailability study, in dosage
Under the premise of identical, which then illustrates bioavilability height, and the numerical value is low to illustrate that bioavilability is low, needs furtherly
Bright, the height of bioavilability of the present invention is indicated using the height of this numerical value.
Specific embodiment
For a further understanding of the present invention, the following describes the present invention in detail with reference to examples.
Embodiment 1
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| PLURONICS F87 | 500g |
Technique:
1) folic acid and PLURONICS F87 of recipe quantity are weighed, first melts PLURONICS F87 completely under the conditions of 65 DEG C,
Then folic acid, stirring to complete melting is added；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 4 hours under the conditions of -15 DEG C；
3) 2 after taking freezing) resulting material takes out after 2 hours dry under the conditions of 35 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 2
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| Macrogol 6000 | 1000g |
Technique:
1) folic acid and Macrogol 6000 of recipe quantity are weighed, first melts Macrogol 6000 completely under the conditions of 80 DEG C
Change, folic acid, stirring to complete melting is then added；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 6 hours under the conditions of -25 DEG C；
3) 2 after taking freezing) resulting material takes out after 6 hours dry under the conditions of 45 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 3
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| PLURONICS F87 | 1500g |
| Macrogol 4000 | 1500g |
Technique:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, first carrier is melted completely under the conditions of 70 DEG C, is then added
Folic acid, stirring to complete melting；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 8 hours under the conditions of -20 DEG C；
3) 2 after taking freezing) resulting material takes out after 4 hours dry under the conditions of 40 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 4
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| PLURONICS F87 | 2000g |
| Macrogol 6000 | 3000g |
Technique:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, first carrier is melted completely under the conditions of 75 DEG C, is then added
Folic acid, stirring to complete melting；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 12 hours under the conditions of -30 DEG C；
3) 2 after taking freezing) resulting material takes out after 6 hours dry under the conditions of 45 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 5
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| Macrogol 4000 | 1500g |
Technique:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, first carrier is melted completely under the conditions of 65 DEG C, is then added
Folic acid, stirring to complete melting；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 8 hours under the conditions of -20 DEG C；
3) 2 after taking freezing) resulting material takes out after 3 hours dry under the conditions of 40 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 6
The preparation of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100.0g |
| Macrogol 4000 | 700g |
| Macrogol 6000 | 800g |
Technique:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, first carrier is melted completely under the conditions of 70 DEG C, is then added
Folic acid, stirring to complete melting；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled under ice bath, stirring condition completely solid
Change, is then freezed 8 hours under the conditions of -20 DEG C；
3) 2 after taking freezing) resulting material takes out after 4 hours dry under the conditions of 40 DEG C, crushes and sieve 80~150
Material within the scope of mesh is to get folic acid solid dispersions.
Embodiment 7
The preparation (polishing) of folic acid solid dispersions:
Prescription:
| Supplementary material | Dosage |
| Folic acid | 100g |
| Mannitol | 1500g |
| PVP K30 | 1500g |
Technique:
1) mannitol, the PVP K30 for weighing recipe quantity are uniformly mixed, are then uniformly mixed again with the folic acid of recipe quantity；
2) 1) the uniformly mixed material of gained is ground 4 hours in ball mill, sieves the object within the scope of 80~150 mesh
Material is to get folic acid solid dispersions.
Embodiment 8
The preparation of Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid solid dispersions-embodiment 5 | 50.0g (in terms of folic acid) |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 100.0g |
Preparation process:
1) starch of recipe quantity, lactose is taken to be uniformly mixed；
2) 5 gained folic acid solid dispersions of the embodiment of recipe quantity are uniformly mixed with 1) resulting material；
3) the magnesium stearate total mix of recipe quantity is added to uniform to 2) resulting material；
4) 3) resulting material tablet press machine is tabletted to get Couteat of Folic Acid.
Embodiment 9
The preparation of Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid solid dispersions-embodiment 6 | 4.0g (in terms of folic acid) |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 100.0g |
Preparation process:
1) starch of recipe quantity, lactose is taken to be uniformly mixed；
2) 6 gained folic acid solid dispersions of the embodiment of recipe quantity are uniformly mixed with 1) resulting material；
3) 2) resulting material is sieved into the particle of 24~65 mesh after dry press dry-pressing and crushing；
4) weighing the magnesium stearate of recipe quantity, to be added into 3) gained particle total mix tabletted with tablet press machine to uniform,
Up to Couteat of Folic Acid.
Embodiment 10
The preparation of folic acid capsule:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid solid dispersions-embodiment 1 | 100g (in terms of folic acid) |
| Microcrystalline cellulose | 1050g |
| Pregelatinized starch | 2000g |
| Superfine silica gel powder | 50.0g |
Preparation process:
1) microcrystalline cellulose of recipe quantity, pregelatinized starch is taken to be uniformly mixed；
2) 1 gained folic acid solid dispersions of the embodiment of recipe quantity are uniformly mixed with 1) resulting material；
3) the differential silica gel total mix of recipe quantity is added to uniform to 2) resulting material；
4) 3) resulting material is filled into capsule shells with capsule filling machine to get folic acid capsule.
Embodiment 11
The preparation of folic acid particle:
Preparation prescription:
| Supplementary material | Recipe quantity (10000 bags) |
| Folic acid solid dispersions-embodiment 7 | 50.0g (in terms of folic acid) |
| Starch | 1050g |
| Lactose | 2000g |
| Corrigent | 50.0g |
| Magnesium stearate | 50.0g |
Preparation process:
1) starch of recipe quantity, lactose is taken to be uniformly mixed；
2) 7 gained folic acid solid dispersions of the embodiment of recipe quantity are uniformly mixed with 1) resulting material；
3) 2) resulting material through dry press dry-pressing and is crushed, sieves the particle of 24~65 mesh；
4) after evenly mixing, and 3) gained particle total mix is to uniform for the corrigent and magnesium stearate for taking recipe quantity, and packing is extremely
To get folic acid particle in aluminum-plastic composite membrane bag.
Embodiment 12
The preparation of folic acid powder:
Preparation prescription:
| Supplementary material | Recipe quantity (10000 bags) |
| Folic acid solid dispersions-embodiment 2 | 2.0g (in terms of folic acid) |
| Starch | 1050g |
| Lactose | 2000g |
| Corrigent | 50.0g |
| Magnesium stearate | 50.0g |
Preparation process:
1) starch of recipe quantity, lactose is taken to be uniformly mixed；
2) 2 gained folic acid solid dispersions of the embodiment of recipe quantity are uniformly mixed with 1) resulting material；
3) corrigent and magnesium stearate for taking recipe quantity after evenly mixing, with 2) resulting material total mix to uniform, cross 100 mesh
Packing is dissipated into aluminum-plastic composite membrane bag to get folic acid after sieve.
Comparative example 1~7
Here, the present inventor uses the prescription of Examples 1 to 7, the technique directly mixed by powder is made respectively
The sample of standby comparative example 1~7 obtains the direct mixed-powder of folic acid with each corresponding hydrophilic carrier preparation.It should be noted that
The prescription of Examples 1 to 7 and comparative example 1~7 is stringent correspondence, for example, comparative example 3 prescription be same embodiment 3 place
Side is completely the same, and the prescription of comparative example 7 is that the prescription of same embodiment 7 is completely the same.
Comparative example 8
The preparation of Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Macrogol 4000 | 750g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 100.0g |
Preparation process:
1) starch for taking recipe quantity is weighed, lactose is uniformly mixed；
2) folic acid of recipe quantity is uniformly mixed with Macrogol 4000
3) 2) resulting material is uniformly mixed with 1) resulting material；
4) the magnesium stearate total mix of recipe quantity is added to uniform to 3) resulting material；
5) 4) resulting material tablet press machine is tabletted to get Couteat of Folic Acid.
Comparative example 9
The preparation of Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 100.0g |
Preparation process:
1) starch for taking recipe quantity is weighed, lactose is uniformly mixed；
2) folic acid of recipe quantity is uniformly mixed with 1) resulting material；
3) the magnesium stearate total mix of recipe quantity is added to uniform to 2) resulting material；
4) 3) resulting material tablet press machine is tabletted to get Couteat of Folic Acid.
Test case 1
It is studied according to stablizing under illumination condition in the test of " chemicals stability study technological guidance principle " influence factor
Method, carry out the light durability research of Examples 1 to 7 and comparative example 1~7, intensity of illumination is 4500Lx ± 500Lx, is taken
Sample detection time is the 0th day, 5 days, 10 days, and detection project is related substance, and detection method is according to 2010 addendum of Chinese Pharmacopoeia
Related substances separation method under Couteat of Folic Acid item carries out, specific testing result such as the following table 1:
1~7 light durability testing result of 1. Examples 1 to 7 of table and comparative example
In comprehensive analysis known to 1 result of table: 1) carry out illumination before, i.e., the 0th day statistics indicate that, Examples 1 to 7 and right
The related substance of ratio 1~7 is that notable difference, pteroic acid, single miscellaneous and total miscellaneous amount are not in almost comparable level.2) will
The sample of Examples 1 to 7 and comparative example 1~7 was exposed to lower 5 days of the intensity of illumination of this test case and after 10 day, comparative example 1~7
The related substance of gained each sample, which has, significantly to be increased, as the amount of 5 pteroic acid of comparative example increases to 0.73% by 0.22%, total miscellaneous
The amount of matter increases to 2.25% by 0.94%, and amplification reaches 2 times or more, there is also the same fact in other comparative examples, this
People is made it difficult for receive in this field；In contrast, the related substance of each solid dispersions obtained by Examples 1 to 7 is only micro-
Amount variation, if the amount of 5 pteroic acid of embodiment becomes 0.32% from 0.20%, the amount of total impurities becomes 1.10% from 0.95%, is based on
The stability study is carried out under violent illumination condition, this variation may be considered unconspicuous, is illustrated of the invention real
It applies 1~7 obtained solid dispersion of example and shows good photostability.3) it is well known that an important physical and chemical feature of folic acid
It is that photostability is poor, this is also the problem that must be faced when preparing its clinical application object, in general, by a kind of photo-labile
Drug is mixed with suitable auxiliary material, can not solve the problems, such as its eventual stabilities, the study on light stability knot of comparative example 1~7
Fruit also further demonstrates this case；It is very joyful, in the embodiment of the present invention 1~7, using technology of the present invention
The sample that scheme obtains, although on material base to each corresponding comparative example indifference, the difference of preparation process, folic acid with
Mutually there is the difference of microstate in hydrophilic carrier, the far apart difference of further bring photostability result is to go out completely
What the present inventor expected.
Test case 2
According to the method for " chemicals stability study technological guidance principle " acceleration for stabilization Journal of Sex Research, embodiment 1 is carried out
~7 and comparative example 1~7 acceleration for stabilization Journal of Sex Research, temperature be 40 DEG C ± 2 DEG C, relative humidity be 75% ± 5%, sample detection
Time is the 0th month, January, 2 months, March, June, and detection project is content and pteroic acid, and detection method is augmented according to Chinese Pharmacopoeia 2010
Content and Related substances separation method under version Couteat of Folic Acid item carry out, specific testing result such as the following table 2:
1~7 accelerated stability testing result of 2. Examples 1 to 7 of table and comparative example
| Sample | 0th month | January | 2nd month | March | June |
| Content | Pteroic acid | Content | Pteroic acid | Content | Pteroic acid | Content | Pteroic acid | Content | Pteroic acid | |
| Embodiment 1 | 100.5% | 0.19% | 100.2% | 0.17% | 100.2% | 0.19% | 100.4% | 0.16% | 100.5% | 0.18% |
| Comparative example 1 | 100.2% | 0.16% | 99.3% | 0.25% | 98.5% | 0.38% | 97.8% | 0.50% | 95.4% | 0.62% |
| Embodiment 2 | 99.5% | 0.15% | 99.2% | 0.17% | 99.8% | 0.16% | 99.5% | 0.16% | 99.7% | 0.18% |
| Comparative example 2 | 99.8% | 0.19% | 99.0% | 0.24% | 97.5% | 0.35% | 96.3% | 0.47% | 95.0% | 0.57% |
| Embodiment 3 | 99.2% | 0.21% | 99.5% | 0.22% | 99.3% | 0.20% | 99.2% | 0.24% | 99.5% | 0.20% |
| Comparative example 3 | 99.7% | 0.23% | 99.0% | 0.27% | 98.2% | 0.32% | 97.3% | 0.40% | 95.6% | 0.54% |
| Embodiment 4 | 100.2% | 0.18% | 99.7% | 0.22% | 100.0% | 0.20% | 100.2% | 0.19% | 100.4% | 0.20% |
| Comparative example 4 | 100.5% | 0.20% | 99.5% | 0.25% | 98.4% | 0.33% | 97.5% | 0.41% | 96.2% | 0.52% |
| Embodiment 5 | 99.6% | 0.20% | 99.5% | 0.23% | 99.8% | 0.21% | 99.6% | 0.20% | 99.3% | 0.24% |
| Comparative example 5 | 99.3% | 0.22% | 98.3% | 0.26% | 97.6% | 0.32% | 96.5% | 0.43% | 95.4% | 0.53% |
| Embodiment 6 | 99.7% | 0.17% | 99.5% | 0.20% | 99.8% | 0.22% | 99.4% | 0.19% | 99.5% | 0.20% |
| Comparative example 6 | 99.5% | 0.23% | 98.4% | 0.26% | 97.5% | 0.34% | 96.4% | 0.40% | 95.7% | 0.55% |
| Embodiment 7 | 100.4% | 0.19% | 100.2% | 0.17% | 100.4% | 0.22% | 100.0% | 0.24% | 100.5% | 0.22% |
| Comparative example 7 | 99.8% | 0.17% | 99.0% | 0.23% | 98.2% | 0.32% | 97.1% | 0.41% | 95.4% | 0.52% |
In comprehensive analysis known to 2 result of table: 1) each folic acid solid dispersions obtained by Examples 1 to 7 accelerated steady at 6 months
During qualitative investigation, the content and impurity pteroic acid of folic acid show good stability, each detection time point folate content, butterfly
The equal no significant difference of amount of acid；2) 1~7 each sample of comparative example, folate content are shown bright during accelerated stability is investigated
Aobvious downward trend, the amount of impurity pteroic acid have the tendency that obviously rising；It is each to compare when accelerated stability was investigated to 6th month
The decline of example folate content is 5% or so, and the increase of impurity pteroic acid also about 2 times substantially of level, such as comparative example 2, leaf
The content of acid drops to 95.0% from 99.8%, totally has dropped 4.8%, the amount of impurity pteroic acid is increased to from 0.19%
0.57%, generally increase 2 times [(0.57%-0.19%)/0.19%]；3) it needs to clarify explanation, this content of folic acid
And the variation of impurity pteroic acid will clinically be brought many detrimental effects, such as the decline of folate content to often mean that clinic
The reduction of curative effect, the increase of impurity pteroic acid amount can then bury great hidden danger to clinical safety.
Test case 3
According to the Content uniformity test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, carry out embodiment 8~
12 and comparative example 8,9 foliamins Content uniformity test, as a result such as the following table 3:
3. embodiment 8~12 of table and comparative example 8,9 foliamin Content uniformity test results
| Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | Comparative example 8 | Comparative example 9 | |
| Average content X | 98.8 | 98.5 | 99.0 | 98.6 | 98.5 | 98.8 | 99.0 |
| A=| 100-X | | 1.2 | 1.5 | 1.0 | 1.4 | 1.5 | 1.2 | 1.0 |
| Standard deviation S | 2.8 | 2.7 | 2.8 | 2.6 | 2.6 | 6.5 | 7.0 |
| A+1.80S | 6.2 | 6.4 | 6.0 | 6.0 | 6.2 | 12.9 | 13.6 |
In synthesis known to 3 interpretation of result of table: using the foliamin of folic acid solid dispersions of the present invention preparation, having
There is good uniformity of dosage units, as a result much smaller than the requirement of A+1.80S≤15 of States Pharmacopoeia specifications；It is worth noting that comparative example 8
Preparation be made of being directly mixed with folic acid and hydrophilic carrier material, the preparation of comparative example 9 is only with folic acid and medicine
Acceptable auxiliary material processing is prepared on, and uniformity of dosage units testing result shows that the two is much larger than embodiment 8~12, and
In the 2 times or more of embodiment 8~12；It is well known that A+1.80S value is a weight for reacting small dimension formulation content uniformity coefficient
Index is wanted, the value is smaller to illustrate that uniformity of dosage units is higher, and consistency is the better in prepared formulation products batch, and the value is higher,
Illustrate that the difference between in prepared formulation products batch is bigger；Further, the difference of uniformity of dosage units is embodied in clinical efficacy
On, then show the difference because of sample room content, it is inconsistent on caused curative effect science, thus will to clinician and patient with
Hidden danger and puzzlement centainly is carried out.
Test case 4
According to the dissolution test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, 8~12 He of embodiment is carried out
The dissolution test of comparative example 8,9 gained foliamins, as a result such as the following table 4:
4. embodiment 7,8 of table and comparative example 1,2 Couteat of Folic Acid dissolution test results
| Dissolution rate | Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | Comparative example 8 | Comparative example 9 |
| 30 minutes | 93.4% | 92.5% | 91.5% | 92.0% | 92.4% | 83.6% | 78.5% |
In synthesis known to 4 interpretation of result of table: 1) dissolution rate of 8~12 gained folic acid solid pharmaceutical preparation of embodiment 90% with
On, dissolution rate with higher, while prompt may have excellent vivo biodistribution availability；2) comparative example 8,9 dissolution rates are equal
Good level far below 90%, 9 dissolution rate of comparative example is only 78.5%, and suitable hydrophily is applied in comparative example 8 and is carried
Body material, but, the favorable attributes to dissolution rate are very faint；3) dissolution rate of integrated embodiment 8~12 and comparative example 8,9
Testing result shows solid dispersions of the present invention, can be beneficial after the final preparation for being prepared as clinically applying
Improve the dissolution rate situation of this insoluble drug of folic acid, the dissolution rate for solving the problems, such as that conventional formulation technologies are difficult to go beyond is low.
Test case 5
According to the method in " chemicals stability study technological guidance principle " and condition is investigated, referring to Chinese Pharmacopoeia
Content, related substance, 30 minutes dissolution test methods in 2010 addendums under Couteat of Folic Acid item, carry out 8~12 He of embodiment
Steadiness under comparative example 8,9 gained foliamin acceleration environments is investigated, as a result such as the following table 5:
5. embodiment 8~12 of table and comparative example 8,9 Couteat of Folic Acid accelerated stability results
In synthesis known to 5 interpretation of result of table: 1) embodiment 8~12 6 months under acceleration conditions, folate content, pteroic acid are miscellaneous
Matter and dissolution rate show good stability；2) comparative example 8, obvious unstable feelings are all had in comparative example 9,6 months
Condition has dropped 4.8% (98.8%-94.0%) in 6 months in terms of content by taking comparative example 8 as an example, in impurity pteroic acid 6 months certainly
0.21% increases to 0.68%, and 7.8% (83.6%-75.8%) is had dropped in dissolution rate 6 months.
Test case 6
It selects Beagle dog as animal subject, studies leaf prepared by embodiment 8~12 and comparative example 8,9 of the present invention
The bioavilability situation of acid supplement needs predeclared to be the implementation of following testing programs Beagle in whole cycle
The raising of dog is all made of same standardized diet, may be adversely affected to result bring with excluding food.
Animal subject selection and grouping: female, health, Beagle dog of the same age are selected, weight is in 10 ± 1.0kg range
It is interior, amount to 42, is randomly divided into 7 groups, every group 6；
Testing program: 1) it tests first 21 day and does not apply any drug；2) it tests first 7 days, 0.1mg folic acid/kg is given once daily
The drug of weight carries out each animal subject background presaturation, and the background folic acid concentration of each animal subject is made to reach the level of stable state；
3) it tests preceding 1 day 20:00 each group animal subject to be fasted, test same day 7:00 give 0.5mg folic acid/kg weight medicine on an empty stomach
Object, and in each sampling time point (0 point, 15 minutes, 30 minutes, 45 minutes, 1.0 hours, 1.5 hours, 2.0 hours, 4.0 hours,
6.0 hours, 8.0 hours, 12.0 hours, 24.0 hours, 48.0 hours), it extracts forelimb median vein 2mL blood and keeps sample；4) it adopts
Folate content inspection is carried out with sample of the commercially available Beagle dog folic acid ELISA kit to each sampling time point of each tested group of animal
Survey, and calculate each tested group 6 each assessment items of Beagle dog mean value, it need to be noted that be sample analysis detect
Before, the methodology that the present inventor has carried out system to the precision of this method, the rate of recovery, specificity, detection limit etc. is tested
Card, the results showed that, which is that science is feasible.
Using the result such as the following table 6 for the Beagle dog bioavailability study that test case of the present invention carries out:
6. embodiment 8~12 of table and comparative example 8,9 bioavailability study results
In synthesis known to 6 interpretation of result of table: 1) the folic acid system of folic acid solid dispersions embodiment 8~12 of the present invention
Agent, faster, show as Tmax is 45 minutes to infiltration rate, and the Couteat of Folic Acid Tmax that comparative example 8,9 is prepared is 1 hour；
2) bioavilability of 8~12 gained foliamin of embodiment is apparently higher than comparative example 8 and 9,8 relative contrast's example 1 of embodiment
Say and improve (118.2-90.6)/90.6=30.5%, improved for 8 relative contrast's example 9 of embodiment (118.2-88.7)/
88.7=33.3%.
Method and core concept of the invention that the above embodiments are only used to help understand.It should be pointed out that for
For those skilled in the art, without departing from the principle of the present invention, if can also be carried out to the present invention
Dry improvement and modification, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (11)
1. a kind of folic acid solid dispersions, are made of folic acid and hydrophilic carrier, the weight ratio of folic acid and hydrophilic carrier is 1: 5
~1: 50；The preparation method of the folic acid solid dispersions includes the following steps:
1) folic acid and hydrophilic carrier of recipe quantity are weighed, first carrier is melted completely under the conditions of 65~80 DEG C, is then added
Folic acid, stirring to complete melting；The hydrophilic carrier be one of poloxamer, polyethylene glycol, povidone, mannitol or
More than one compositions；
2) 1) gained melting complete folic acid and hydrophilic carrier are rapidly cooled to be fully cured under ice bath, stirring condition,
Then it is freezed 4~12 hours under the conditions of -15~-30 DEG C；
3) 2 after taking freezing) resulting material takes out after dry 2~6 hours under the conditions of 35~45 DEG C, crush and sieve 80~
Material within the scope of 150 mesh is to get folic acid solid dispersions.
2. folic acid solid dispersions according to claim 1, which is characterized in that the weight ratio of the folic acid and hydrophilic carrier
It is 1: 10~1: 30.
3. folic acid solid dispersions described in any one according to claim 1~2, which is characterized in that the solid dispersions
Size distribution is within the scope of 80~150 mesh.
4. folic acid solid dispersions according to claim 2, which is characterized in that the weight ratio of the folic acid and hydrophilic carrier
It is 1: 15.
5. folic acid solid dispersions according to claim 1, which is characterized in that the hydrophilic carrier be PLURONICS F87,
One of Macrogol 4000, Macrogol 6000 or more than one compositions.
6. folic acid solid dispersions according to claim 1, which is characterized in that the system of the folic acid solid dispersions clinically
Dosage form formula is oral solid formulation.
7. folic acid solid dispersions according to claim 6, which is characterized in that contain in the oral solid formulation unit formulation
0.2~10.0mg of folic acid.
8. folic acid solid dispersions according to claim 7, which is characterized in that contain in the oral solid formulation unit formulation
0.4~5.0mg of folic acid.
9. folic acid solid dispersions according to claim 6, which is characterized in that the oral solid formulation includes pharmaceutically may be used
The excipient for preparations shaping received.
10. folic acid solid dispersions according to claim 6, which is characterized in that the oral solid formulation 30 minutes molten
Out-degree is not less than 90%.
11. according to folic acid solid dispersions described in claim 7~10 any one, which is characterized in that the oral administration solid system
Agent is not limited to tablet, capsule, granule, powder.
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