CN105496941B - A kind of folic acid solid pharmaceutical preparation and preparation method thereof - Google Patents
A kind of folic acid solid pharmaceutical preparation and preparation method thereof Download PDFInfo
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- CN105496941B CN105496941B CN201410499518.4A CN201410499518A CN105496941B CN 105496941 B CN105496941 B CN 105496941B CN 201410499518 A CN201410499518 A CN 201410499518A CN 105496941 B CN105496941 B CN 105496941B
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- folic acid
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- magnesium stearate
- starch
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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 480
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 243
- 239000011724 folic acid Substances 0.000 title claims abstract description 243
- 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 238
- 229960000304 folic acid Drugs 0.000 title claims abstract description 238
- 238000002360 preparation method Methods 0.000 title claims abstract description 93
- 239000007787 solid Substances 0.000 title claims abstract description 38
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 62
- 239000000463 material Substances 0.000 claims abstract description 53
- 238000012545 processing Methods 0.000 claims abstract description 43
- 238000009826 distribution Methods 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 238000004090 dissolution Methods 0.000 claims abstract description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 102
- 235000019359 magnesium stearate Nutrition 0.000 claims description 51
- 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 claims description 47
- 239000008101 lactose Substances 0.000 claims description 47
- 239000002245 particle Substances 0.000 claims description 41
- 229920002472 Starch Polymers 0.000 claims description 38
- 239000008107 starch Substances 0.000 claims description 38
- 235000019698 starch Nutrition 0.000 claims description 38
- 238000007908 dry granulation Methods 0.000 claims description 18
- 238000003801 milling Methods 0.000 claims description 18
- 238000003825 pressing Methods 0.000 claims description 13
- 238000005453 pelletization Methods 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims 3
- 238000012216 screening Methods 0.000 claims 3
- 239000007916 tablet composition Substances 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 15
- 230000008901 benefit Effects 0.000 abstract description 7
- 238000009472 formulation Methods 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 77
- 230000008569 process Effects 0.000 description 33
- 238000012360 testing method Methods 0.000 description 30
- 239000000126 substance Substances 0.000 description 25
- 235000019580 granularity Nutrition 0.000 description 23
- 239000003814 drug Substances 0.000 description 20
- 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
- 238000000926 separation method Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000012535 impurity Substances 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 13
- 239000008108 microcrystalline cellulose Substances 0.000 description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 13
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- 239000000543 intermediate Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000007922 dissolution test Methods 0.000 description 11
- 238000005550 wet granulation Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 7
- 239000013049 sediment Substances 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 239000000853 adhesive Substances 0.000 description 5
- 230000001070 adhesive effect Effects 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
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- 238000007906 compression Methods 0.000 description 3
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- 238000013461 design Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 239000013020 final formulation Substances 0.000 description 3
- 229940014144 folate Drugs 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 239000002002 slurry Substances 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
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229940121657 clinical drug Drugs 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- -1 corrigent Polymers 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000003929 folic acid group Chemical group 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 229940080428 lactose 200 mg Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 231100001016 megaloblastic anemia Toxicity 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
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- 230000036470 plasma concentration Effects 0.000 description 2
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- 230000002265 prevention Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 239000011782 vitamin Substances 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
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000040350 B family Human genes 0.000 description 1
- 108091072128 B family Proteins 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 244000300264 Spinacia oleracea Species 0.000 description 1
- 235000009337 Spinacia oleracea Nutrition 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 235000014897 Streptococcus lactis Nutrition 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 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
- 230000033228 biological regulation Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
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- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940019142 folic acid 5 mg Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940040511 liver extract Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000276 neural tube Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000000079 presaturation Methods 0.000 description 1
- 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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- 235000019159 vitamin B9 Nutrition 0.000 description 1
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- 150000003722 vitamin derivatives Chemical class 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to pharmaceutical technology field more particularly to a kind of folic acid solid pharmaceutical preparation and preparation method thereof, the folic acid solid pharmaceutical preparation is prepared by folic acid and pharmaceutically acceptable auxiliary material through suitable technique processing；90% or more the granularity of the folic acid is in the distribution of 80-200 mesh；0.20-30.0mg containing folic acid in the folic acid solid pharmaceutical preparation unit formulation, surplus are made of pharmaceutically acceptable auxiliary material.By the folic acid of size distribution of the present invention and pharmaceutically acceptable auxiliary material, the folic acid solid pharmaceutical preparation obtained using the suitable preparation process, 30 minutes dissolution rates are not less than 85%, not only there is clinical advantage safely, effectively, quality controllable, also there is less energy consumption, comprehensive advantage that is environmental-friendly, being easy to realization of industrialization.
Description
Technical field
The present invention relates to pharmaceutical technology fields more particularly to a kind of folic acid solid pharmaceutical preparation 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(structural formula such as following formula), 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
Embodiment is not only determined by active constituent itself, is also administered with it, dosage form even production technology has close relationship.Mesh
Before, the main form of medication of folic acid clinically is oral solid tablet, the main manufacturer of domestic commercially available folic acid include Beijing this
Li An pharmaceutcal corporation, Ltd, Shenyang Gelin Pharmaceutical Co., Ltd., Huabei Pharmaceutic Co., Ltd, Jiangxi pharmacy Limited Liability are public
Department etc., dosage form is oral solid tablet, and specification includes 0.4mg and 5.0mg, belongs to generally acknowledged small dimension preparation, by existing
Row Chinese Pharmacopoeia regulation, needs to carry out the inspection of its uniformity of dosage units, meanwhile, existing Chinese Pharmacopoeia is it further provides that carry out its preparation
Impurity and dissolution test.The formulation of one clinical medicine quality standard and bound requirements are based on the progress of drug the characteristics of itself
, such as physicochemical property and biological property etc..According to the structure feature of existing research and folic acid, folic acid known to analysis is a kind of
The change of very poor stability is shown as to light, heat and wet (being embodied as water) and organic solvent (such as methanol, ethyl alcohol) etc.
Learn substance；Current commercial Couteat of Folic Acid is small dimension preparation, and generally, small dimension preparation is not easy using non-wet granulation technology
It is uniformly mixed, therefore, the technique that presently commercially available Couteat of Folic Acid is all made of wet granulation prepares foliamin, inevitably applies
Water or organic solvent are inevitably exposed to again under the environment of heat in particle drying procedures, give technical process and finished product
Preparation and clinical application bring huge safety risks, do not meet the requirement that current Quality is derived from advanced design theory；Together
When, in terms of biological property, the characteristics of dissolution low-permeability low because of folic acid, determining it, bioavilability is relatively in vivo
Low objective fact (medically it has been generally acknowledged that bioavilability is the direct determinant of clinical drug curative effect), finally, folic acid
Low vivo biodistribution availability further resulted in the limitation that its clinical efficacy cannot be not fully exerted.
Shenyang Gelin Pharmaceutical Co., Ltd.'s application " a kind of Couteat of Folic Acid and preparation method thereof " (application number:
201110280578.3) wet granulation technology in patent using 60% ethyl alcohol as adhesive prepares folic acid wet granular, then
It is further tabletted in 55-65 DEG C of dry dry particl, obtain the folic acid with good uniformity of dosage units and dissolution rate
Piece；But the impurity and bioavilability situation that Couteat of Folic Acid is not specified in patent, are analyzed it is found that 60% ethyl alcohol and temperature 55-65
It DEG C is two key factors for influencing folic acid stability, this is very unfavorable for the impurity for controlling product；In addition, in patent
Point out gained Couteat of Folic Acid dissolution rate 95% or more, however, it is this kind of for folic acid it is low dissolution low-permeability drug for,
The case where In vitro-in vivo correlation is often poor, and external dissolution rate can not definitely prompt vivo biodistribution availability, and it is final anti-
It should be on clinical efficacy.
Hua'anfo Medicine Research Center Co., Ltd., Beijing application " folic acid dropping pill and preparation method thereof " (application number:
200610099026.1), " a kind of folic acid effervescent tablet and preparation method thereof " (application of Guangdong Shixin Pharmaceutical Co., Ltd.'s application
Number: 200710107195.X), " a kind of folic acid pellet and its system of Tianjin Fulande Medical Science & Technology Development Co., Ltd.'s application
Preparation Method " (application number: 200810182808.0), " folic acid enteric preparation of Beijing Ruiyiren Science and Technology Development Co., Ltd.'s application
Composition and preparation method thereof " (application number: 200810117696.0), has inevitably used shadow in technical process
The condition for ringing folic acid stability brings the wind that can not evade to product including the high temperature in ethyl alcohol, water and particle drying procedures
Danger.
It is well known that clinically ideal drug should be safely, effectively, it is quality controllable, and the risk of safety is main
It is as caused by impurity, the embodiment of validity depends primarily on galenic pharmacy feature of the drug with drug itself, and quality controllability is then
It is to be determined by the technological design and technical process of medicine preparation.In summary, it there is no effective technological means for clinic at present
On a kind of folic acid drug of more advantage is provided, therefore, currently there is an urgent need to provide it is a kind of have impurity few, highly-safe, it is raw
Object availability is high, validity is good, and stable technical process, reproducibility be good, the ideal folic acid drug of the clinical advantages such as quality controllable
Preparation, while less energy consumption, comprehensive advantage that is environmental-friendly and being easy to realization of industrialization should be met.
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 pharmaceutical preparations and preparation method thereof.
In order to solve the above technical problems, the present invention uses following technical scheme, a kind of folic acid solid pharmaceutical preparation.
The solid pharmaceutical preparation is folic acid by 90% or more size distribution within the scope of 80-200 mesh and pharmaceutically acceptable
Auxiliary material processing be prepared；
Preferably, the size distribution of the folic acid is 90% or more within the scope of 100-150 mesh.
0.20-30.0mg containing folic acid in the folic acid solid pharmaceutical preparation unit formulation；
Preferably, 0.40-10.0mg containing folic acid in the folic acid solid pharmaceutical preparation unit formulation.
The pharmaceutically acceptable auxiliary material includes starch, pregelatinized starch, microcrystalline cellulose, lactose, hypromellose
One of element, povidone, sodium carboxymethylcellulose, povidone, magnesium stearate, talcum powder, corrigent or more than one combinations
Object；
Preferably, the pharmaceutically acceptable auxiliary material include one of starch, lactose, magnesium stearate or more than one
Composition.
Solid pharmaceutical preparation of the present invention includes but is not limited to tablet, capsule, granule, dry suspensoid agent.
Preferably, the solid pharmaceutical preparation is tablet.
Tablet of the present invention can be prepared by powder vertical compression technique, the processing of dry granulation tablet forming technique.
Preferably, the tablet is prepared by the processing of dry granulation tablet forming technique.
The tablet of dry granulation tablet forming technique preparation of the present invention, 30 minutes dissolution rates are not less than 85%.
Preferably, tablet of the present invention can be prepared by following unit formulation composition:
Folic acid 0.40mg, starch 105mg, lactose 200mg, magnesium stearate 5.00mg.
Preferably, the tablet can be prepared by following unit formulation composition:
Folic acid 5mg, starch 100mg, lactose 200mg, magnesium stearate 5.00mg.Tablet of the present invention can be by following dry method
Pelletizing press sheet technique is prepared:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 10-30 minutes
Tabletting is afterwards to get the Couteat of Folic Acid.
The folic acid solid pharmaceutical preparation of the present invention obtained by adopting the above technical scheme can preferably generate the present invention and be wanted
The purpose and technical effect reached, specifically, a kind of folic acid solid pharmaceutical preparation of the present invention and preparation method thereof can generate:
1) gained folic acid solid pharmaceutical preparation impurity is few, highly-safe；2) dissolution rate and bioavilability are high, and Clinical efficacy is good；3) work
Skill process is stablized, and quality reproduction is good, quality controllable advantageous effects；Further, a kind of folic acid solid of the present invention
Preparation and preparation method thereof also has less energy consumption, environmental-friendly, is easy to industrialize amplification 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；
" unit formulation ": referring to the per unit preparation of the folic acid solid pharmaceutical preparation, such as refer to 1 for tablet, capsule
Agent refers to 1, and granule, dry suspensoid agent refer to 1 bag；
" corrigent ": referring to pharmaceutically acceptable for improving material, including sweetener, essence of mouthfeel etc., does not limit to
In a certain or a certain classification, dosage is for the purpose of generating the acceptable mouthfeel of patient, the people of technical field of the present invention
Member is attempted by simply test, that is, can determine the type and dosage of corrigent；
" 90% or more size distribution is in 80-200 mesh ": refer to that the granularity of powder or particle has 90% or more in 80-200 purpose
In range, it is understood that for other than 80-200 mesh powder or particle below 10%；
" Tmax ": time when drug after medicine reaches maximum plasma concentration is showed；
" Cmax ": the maximum plasma concentration detected after medicine in body is showed；
“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.
Folic acid solid pharmaceutical preparation provided by the invention and preparation method thereof uses in the prescription of the folic acid solid pharmaceutical preparation
Folic acid is the folic acid of specified particle size distribution, and the preparation method is not using being related to heat, water or organic solvent in technical process
Technique.
Folic acid raw material in folic acid solid pharmaceutical preparation prescription of the present invention is 90% crushed and screened by airflow milling
Folic acid of the above size distribution within the scope of 80-200 mesh, and according to the difference of raw material granularity, the granularity of auxiliary material is controlled in spy
In fixed range, to solve, well known to a person skilled in the art small dimension preparations to be difficult to solve using non-wet granulation technology
Technical problem.By taking following embodiments 7 as an example, folate content is only 0.4mg in unit formulation part, belongs to the system of minimum specification
Agent, uniformity of dosage units problem are extremely difficult to resolve certainly, and after by a large amount of creative work, discovery is worked as adopts the present inventor
With 90% or more size distribution when the folic acid raw material of 100-150 mesh prepares Couteat of Folic Acid, by used auxiliary material lactose, starch,
Dolomol can solve the problems, such as uniformity of dosage units by 120 meshes；The present inventor also once attempted by lactose,
Starch, magnesium stearate granularity cross 80 meshes or 150 meshes solve the problems, such as uniformity of dosage units, but it is disappointed to produce cold people
As a result；Therefore, it is necessary to special instructions, in order to solve the problems, such as uniformity of dosage units, the control of the granularity and auxiliary material granularity of raw material
System is closely related, and needs in the case where specific granularity condition cooperates, and just can get the content using dry granulation process preparation
The small dimension Couteat of Folic Acid of uniformity qualification.
Additionally, it is well known that folic acid be to heat, water and light it is extremely unstable, therefore, folic acid solid pharmaceutical preparation of the present invention
Preparation method in, based on quality derived from design theory institute preferably technique effectively prevent folic acid unfavorable factor
It is existing, the stability of technical process is efficiently solved, the quality controllability of product is improved；It needs herein it is emphasized that originally
Known in the technical staff of field, the distribution of raw material granularity is to have significantly to preparation vivo biodistribution availability for insoluble drug
It influences, research of the present inventor Jing Guo following each specific embodiments has also discovered this phenomenon, the results showed that, this
The preparation bioavilability with higher for inventing the folic acid preparation in the particle size distribution, deviates this size distribution model
Folic acid raw material in enclosing produces the fact that declined bioavailability of oral administration is reduced levels；Meanwhile by a large amount of creative labor
After dynamic, the present inventor is had been surprisingly found that, folic acid solid pharmaceutical preparation vivo biodistribution availability of the present invention is not only by folic acid original
The influence of material granularity distribution, and its preparation process and method also have bioavilability and influence extremely significantly, such as implement
Example 8 and comparative example 2 use identical prescription to prepare Couteat of Folic Acid, and the size distribution of folic acid and each auxiliary material is also consistent in prescription
, but, it can be found that the biology for the Couteat of Folic Acid that embodiment of the present invention 8 is prepared using dry granulation process in test case
Availability is apparently higher than comparative example 2 using the Couteat of Folic Acid of wet granulation technology preparation, for comparative example 2, embodiment 8
Bioavilability improves 40.9%, this be exceed completely the present inventor expect and it is infusive.
In the following, the personnel for the ease of the technical field of the invention understand that the present invention, the present invention provide following specific real
Mode is applied to be described further described folic acid solid pharmaceutical preparation and preparation method thereof:
Embodiment 1
The preparation of powder vertical compression technique Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Lactose | 1000g |
| Magnesium stearate | 30.0g |
| PVP K30 | 70.0g |
| Microcrystalline cellulose | 2000g |
Preparation process:
1) appropriate folic acid raw material is crushed using airflow milling, sieves 90% or more size distribution within the scope of 80-120 mesh
Part is kept in dark place spare；
2) appropriate lactose, povidone, microcrystalline cellulose, magnesium stearate are crossed into 80 meshes respectively, it is spare；
3) weigh the 1 of recipe quantity) gained folic acid raw material and recipe quantity 2) gained PVP K30 be uniformly mixed；
4) the 2 of recipe quantity are weighed) gained lactose and microcrystalline cellulose be uniformly mixed；
5) 3) resulting material is mixed using equivalent gradually-increased to the 15% of prescription total amount with 4) resulting material, with residue
The 4 of amount) magnesium stearate is added in resulting material after mixing, and total mix 20 minutes to get mixed uniformly intermediate；
6) tablet press machine is used, by 5) gained intermediate by the tabletting of 315mg slice weight to get powder vertical compression Couteat of Folic Acid.
Embodiment 2
The preparation of folic acid dry suspensoid agent:
Preparation prescription:
| Supplementary material | Recipe quantity (10000 bags) |
| Folic acid | 100g |
| Starch | 1300g |
| Lactose | 1400g |
| Corrigent | 60.0g |
| Sodium carboxymethylcellulose | 140g |
Preparation process:
1) appropriate folic acid raw material is crushed using airflow milling, sieves 90% or more size distribution within the scope of 120-150 mesh
Part, be kept in dark place spare；
2) appropriate amount of starch, lactose, corrigent, sodium carboxymethylcellulose are sieved with 100 mesh sieve respectively, it is spare；
3) weigh the 1 of recipe quantity) gained folic acid raw material and recipe quantity 2) gained corrigent equivalent gradually-increased be uniformly mixed；
4) the 2 of recipe quantity are weighed) gained sodium carboxymethylcellulose be uniformly mixed with 3) resulting material；
5) by the 2 of 4) resulting material and recipe quantity) gained starch, lactose total mix 15 minutes to get mixed uniformly centre
Body；
6) 5) gained intermediate is dispensed into aluminum-plastic composite membrane bag by 300mg/ bags to get folic acid dry suspensoid agent.
Embodiment 3
The preparation of dry granulation process folic acid granule:
Preparation prescription:
| Supplementary material | Recipe quantity (10000 bags) |
| Folic acid | 2.0g |
| Lactose | 1600g |
| Talcum powder | 20.0g |
| Magnesium stearate | 40.0g |
| Microcrystalline cellulose | 1400g |
| Hydroxypropyl methylcellulose | 40.0g |
Preparation process:
1) appropriate folic acid raw material is crushed using airflow milling, sieves 90% or more size distribution within the scope of 100-120 mesh
Part, be kept in dark place spare；
2) appropriate lactose, talcum powder, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose are sieved with 100 mesh sieve respectively, it is standby
With；
3) the 2 of recipe quantity are weighed) gained talcum powder, magnesium stearate be uniformly mixed；
4) by the 1 of recipe quantity) gained folic acid with 2) obtained by hydroxypropyl methylcellulose be uniformly mixed using equivalent gradually-increased, then with
The 2 of recipe quantity) gained lactose, microcrystalline cellulose be uniformly mixed；
5) 4) resulting material is sieved into the particle of 50-80 mesh, then total with 3) resulting material after dry press dry-pressing and crushing
Mix to uniform, by 310.2mg/ it is packed into aluminum-plastic composite membrane bag to get folic acid granule.
Embodiment 4
The preparation of dry granulation process folic acid capsule:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 4.0g |
| Lactose | 1500g |
| Talcum powder | 20.0g |
| Magnesium stearate | 40.0g |
| Microcrystalline cellulose | 1500g |
| Hydroxypropyl methylcellulose | 30.0g |
Preparation process:
1) appropriate folic acid raw material is crushed using airflow milling, sieves 90% or more size distribution within the scope of 100-150 mesh
Part, be kept in dark place spare；
2) appropriate lactose, talcum powder, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose are sieved with 100 mesh sieve respectively, it is standby
With；
3) by the 1 of recipe quantity) gained folic acid with 2) obtained by hydroxypropyl methylcellulose be uniformly mixed using equivalent gradually-increased, then with
The 2 of recipe quantity) gained lactose, microcrystalline cellulose be uniformly mixed；
4) 3) resulting material through dry press dry-pressing and is crushed, cross 65 meshes after again with recipe quantity 2) gained talcum powder,
Magnesium stearate total mix is refilled by the grain of 309.4mg with capsule filler and fills capsule to get folic acid capsule to uniform.
Embodiment 5
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 300g |
| Magnesium stearate | 40.0g |
| Microcrystalline cellulose | 1500g |
| Pregelatinized starch | 1200g |
| Hydroxypropyl methylcellulose | 60.0g |
Preparation process:
1) appropriate folic acid raw material is crushed using airflow milling, sieves 90% or more size distribution within the scope of 150-200 mesh
Part, be kept in dark place spare；
2) suitable magnesium stearate, microcrystalline cellulose, pregelatinized starch, hydroxypropyl methylcellulose are crossed into 120 meshes respectively, it is spare；
3) weigh the 1 of recipe quantity) gained folic acid and the 2 of recipe quantity) gained hydroxypropyl methylcellulose be uniformly mixed；
4) by the 2 of recipe quantity) gained microcrystalline cellulose, pregelatinized starch be uniformly mixed with 3) resulting material；
5) 4) resulting material is sieved into the particle of 24-65 mesh after dry press dry-pressing and crushing；
6) the 2 of recipe quantity are weighed) gained magnesium stearate is added into 5) gained particle total mix and pressed with tablet press machine to uniform
310mg slice weight is tabletted to get Couteat of Folic Acid.
Embodiment 6
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 100.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 10-20 minutes
Afterwards by the tabletting of 320mg slice weight to get the Couteat of Folic Acid.
Embodiment 7
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 4.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 20-30 minutes
Afterwards by the tabletting of 310.4mg slice weight to get the Couteat of Folic Acid.
Embodiment 8
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 15-25 minutes
Afterwards by the tabletting of 315mg slice weight to get the Couteat of Folic Acid.
Comparative example 1
The preparation of wet granulation technology Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 4.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
| 10% starch slurry | In right amount |
Preparation process:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) appropriate 10% Starchy pulps solution is prepared as adhesive using rushing slurry processes；
3) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
4) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
5) homogeneous mixture of material obtained by step 4) is prepared wet through oscillating granulator using 10% starch slurry as adhesive
Grain；
6) wet granular obtained by step 5) is 2 hours dry at 60 DEG C, and of the screen size within the scope of 24-65 mesh
Grain；
7) particle obtained by step 6) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 20-30 minutes
Afterwards by the tabletting of 310.4mg slice weight to get the Couteat of Folic Acid.
Comparative example 2
The preparation of wet granulation technology Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
| 3% hydroxypropyl methylcellulose ethanol solution | In right amount |
Preparation process:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) the hydroxypropyl methylcellulose solution that the ethyl alcohol compound concentration for using 95% is 3% is as adhesive；
3) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
4) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
5) by homogeneous mixture of material obtained by step 4) using 3% hydroxypropyl methylcellulose solution as adhesive, through swing granulation
Machine prepares wet granular；
6) wet granular obtained by step 5) is 1 hour dry at 55 DEG C, and of the screen size within the scope of 24-65 mesh
Grain；
7) particle obtained by step 6) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 15-25 minutes
Afterwards by the tabletting of 315mg slice weight to get the Couteat of Folic Acid.
Comparative example 3
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 4.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is smashed it through into 60 meshes through airflow milling, and it is spare that starch, lactose, magnesium stearate crossed 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 20-30 minutes
Afterwards by the tabletting of 310.4mg slice weight to get the Couteat of Folic Acid.
Comparative example 4
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is smashed it through into 200 meshes through airflow milling, and it is spare that starch, lactose, magnesium stearate crossed 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 15-25 minutes
Afterwards by the tabletting of 315mg slice weight to get the Couteat of Folic Acid.
Comparative example 5
The preparation of dry granulation process Couteat of Folic Acid:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation process:
1) folic acid is sieved after airflow milling crushes 70% or more size distribution 100-150 mesh folic acid, and will form sediment
It is spare that powder, lactose, magnesium stearate cross 120 meshes；
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed；
3) folic acid of the recipe quantity after step 1) processing is weighed to mix with step 2) resulting material using equivalent gradually-increased
It is even；
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0.5-1.5Mpa pressure, is sieved
Collect particle of the granularity within the scope of 24-65 mesh；
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix 15-25 minutes
Afterwards by the tabletting of 315mg slice weight to get the Couteat of Folic Acid.
Before carrying out following test cases 1 and 2, it should be noted that the present inventor is by institute in test case 1 and 2
Intermediate is stated to be defined as above-mentioned each preparation embodiment and prepare the material in comparative example after total mix；Explanation is additionally needed, under
It states in each test case, the pteroic acid is a kind of known impurities of folic acid, and the list is miscellaneous to be referred to and detect in analysis test process
Maximum single impurity, the total impurities refer to comprising pteroic acid, single miscellaneous and other impurities total impurities, the Related substances separation
Refer to pteroic acid, single miscellaneous and total miscellaneous test-based examination.
Test case 1
Intermediate Related substances separation:
According to the Related substances separation method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, embodiment 7,8 and are carried out
The Related substances separation of intermediate in comparative example 1,2 technical process, as a result such as the following table 1:
1. embodiment 7,8 of table and comparative example 1,2 intermediate Related substances separation results
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Pteroic acid | 0.11% | 0.13% | 0.48% | 0.35% |
| It is single miscellaneous | 0.23% | 0.22% | 0.75% | 0.54% |
| It is total miscellaneous | 0.65% | 0.68% | 1.74% | 1.37% |
In comprehensive analysis known to 1 inspection result of table: 1) embodiment 7 of the present invention, embodiment 8 use the work of dry granulation
The midbody particle of skill preparation is significantly less than comparative example 1, comparative example 2 using wet in pteroic acid, single miscellaneous and total impurities amount
The midbody particle of the technique preparation of method granulation, in terms of objective examination's the data obtained, comparative example 1, the related object of the items of comparative example 2
Matter is in the 2 times or more of embodiment 7,8；2) further analysis, comparative example 1 carry out wet process system using 10% Starchy pulps solution
Grain, comparative example 2 carry out wet granulation using 3% hydroxypropyl methylcellulose ethanol solution, and Related substances separation is the result shows that making
The contact of organic solvent and be lesser for being related to the influence to folic acid stability relative to water in standby technical process, but, with
Embodiment 7,8 is compared, and the application of second alcohol and water produces very detrimental effect to the preparation process of preparation, shows as butterfly
Sour, single miscellaneous, always miscellaneous amount is relatively high.It is well known that the height in relation to content of material directly determines the quality of product and faces
Bed safety, this high objective fact of the related content of material of wet granulation technology process intermediates, to final preparation and its
Clinical application brings huge security risk.
Test case 2
Intermediate Related substances separation:
According to the Related substances separation method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, the present inventor is also
The Related substances separation of intermediate in embodiment 1-6 and comparative example 3-5 technical process is carried out, as a result such as the following table 2:
2. embodiment 1-6 of table and comparative example 3-5 intermediate Related substances separation result
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Comparative example 3 | Comparative example 4 | Comparative example 5 |
| Pteroic acid | 0.17% | 0.20% | 0.19% | 0.24% | 0.17% | 0.22% | 0.24% | 0.23% | 0.24% |
| It is single miscellaneous | 0.35% | 0.36% | 0.40% | 0.42% | 0.38% | 0.45% | 0.45% | 0.48% | 0.50% |
| It is total miscellaneous | 0.87% | 0.82% | 0.86% | 0.80% | 0.78% | 0.92% | 0.95% | 0.90% | 0.93% |
Each embodiment of table 2 and comparative example midbody particle Related substances separation result are known in comprehensive analysis: embodiment 1-6
And comparative example 3-5 does not apply water or organic solvent in technical process, therefore, in each embodiment and preparation example technical process
Show relatively good stability, it is pteroic acid, single miscellaneous and total miscellaneous horizontal in a lower level, pteroic acid 0.25% with
Under, it is single miscellaneous not higher than 0.50%, it is always miscellaneous to be below 1.00%.
Test case 3
The related substance of preparation and Content uniformity test:
According to the Related substances separation method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, embodiment 7,8 and are carried out
The Related substances separation of comparative example 1,2 gained Couteat of Folic Acid, as a result such as the following table 3:
3. embodiment 7,8 of table and comparative example 1,2 Couteat of Folic Acid Related substances separation results
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Pteroic acid | 0.14% | 0.15% | 0.58% | 0.46% |
| It is single miscellaneous | 0.26% | 0.23% | 0.94% | 0.83% |
| It is total miscellaneous | 0.73% | 0.75% | 1.87% | 1.65% |
In synthesis in table 3 and test case 1 known to the result of table 1: 1) comparative example 1,2 is prepared by midbody particle processing
After final formulation finished product, pteroic acid, it is single it is miscellaneous, it is total it is miscellaneous have a degree of rising, this is because containing not completely removing in intermediate
Water or organic solvent, tableting processes since violent mechanical condition generates a large amount of heat, and in suitable quantity of water or organic solvent
Caused by folic acid is degraded under conditions of contact；2) further analysis, embodiment 7,8 are prepared into end in midbody particle processing
After finished dosage form, pteroic acid, it is single it is miscellaneous, it is total it is miscellaneous do not occur significant change, show good technology stability；3) by embodiment 7,8
With comparative example 1,2 comparative analyses, embodiment 7, the pteroic acid of 8 final formulation finished products, list are miscellaneous, total miscellaneous significant lower, specifically,
In comparative example 1,2 1/2 hereinafter, this it is all right with the Control of Impurities of midbody particle in technical process be to be closely related
, in other words for, illustrating that influence of the technical process to final preparation is is tool to the control of the quality of product very significantly
The necessity being of practical significance.
According to the Content uniformity test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, embodiment 7,8 is carried out
With the Content uniformity test of comparative example 1,2 Couteat of Folic Acid, as a result such as the following table 4:
4. embodiment 7,8 of table and comparative example 1,2 Couteat of Folic Acid Content uniformity test results
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Average content X | 98.5 | 98.3 | 97.5 | 98.0 |
| A=| 100-X | | 1.5 | 1.7 | 2.5 | 2.0 |
| Standard deviation S | 3.00 | 2.85 | 2.96 | 2.89 |
| A+1.80S | 6.90 | 6.83 | 7.83 | 7.20 |
In synthesis known to 4 interpretation of result of table: under conditions of folic acid specified particle size of the present invention distribution, and suitable control
It is equal to all have good content using the embodiment of the present invention 7 of dry granulation preparation, 8 gained Couteat of Folic Acid for the grain size characteristic of auxiliary material
Evenness as a result much smaller than the requirement of A+1.80S≤15 of States Pharmacopoeia specifications, while slightly using wet granulation institute better than comparative example 1,2
The Couteat of Folic Acid of preparation.
Test case 4
The related substance of preparation and Content uniformity test:
According to the Related substances separation method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, the present inventor is also
It is carried out the Related substances separation of Couteat of Folic Acid obtained by a 1-6 and comparative example 3-5, as a result such as the following table 5:
5. embodiment 1-6 of table and comparative example 3-5 Couteat of Folic Acid Related substances separation result
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Pteroic acid | 0.19% | 0.22% | 0.21% | 0.25% | 0.18% | 0.24% | 0.26% | 0.25% | 0.27% |
| It is single miscellaneous | 0.37% | 0.39% | 0.42% | 0.45% | 0.40% | 0.47% | 0.48% | 0.51% | 0.53% |
| It is total miscellaneous | 0.89% | 0.86% | 0.90% | 0.85% | 0.81% | 0.96% | 0.98% | 0.94% | 0.97% |
In synthesis in table 5 and test case 3 known to the result of table 3: embodiment 1-6 and comparative example 3-5 are by midbody particle
Processing be prepared into pteroic acid after final formulation finished product, it is single it is miscellaneous, it is total it is miscellaneous have no significant change, show good technology stability.
According to the Content uniformity test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, the present inventor
It is also carried out the Content uniformity test of a 1-6 and comparative example 3-5 folic acid solid pharmaceutical preparation, as a result such as the following table 6:
6. embodiment 1-6 of table and comparative example 3-5 Couteat of Folic Acid Content uniformity test result
In synthesis known to 6 interpretation of result of table: embodiment 1-6 and comparative example 3,5 all have good uniformity of dosage units, as a result
Much smaller than the requirement of A+1.80S≤15 of States Pharmacopoeia specifications.
Test case 5
Preparation dissolution test:
According to the dissolution test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, embodiment 7,8 and right is carried out
The dissolution test of Couteat of Folic Acid obtained by ratio 1-5, as a result such as the following table 7:
7. embodiment 7,8 of table and comparative example 1,2 Couteat of Folic Acid dissolution test results
| Dissolution rate | Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 |
| 30 minutes | 94.5% | 95.3% | 83.2% | 84.1% | 70.9% | 90.4% | 78.5% |
In synthesis known to 7 interpretation of result of table: 1) embodiment 7,8 gained Couteat of Folic Acid of embodiment dissolution rate 90% with
On, dissolution rate with higher, while prompt may have excellent vivo biodistribution availability；Analyze comparative example 7,8 and
Comparative example 1,2 Couteat of Folic Acid dissolution results are it is found that be above wet process using 30 minutes dissolution rates of Couteat of Folic Acid obtained by dry granulation
Pelletize comparative example 1,2 Couteat of Folic Acid dissolution rate 10% or more；2) comparative example 7,8 and 3,4,5 Couteat of Folic Acid of comparative example are analyzed
Dissolution results it is found that the particle size and its distribution of folic acid raw material has the dissolution rate of folic acid solid pharmaceutical preparation significantly influences,
The present inventor has been surprisingly found that the folic acid only in particle size range of the present invention has optimal dissolution rate；3) spy is needed
Do not mentionlet alone it is bright, it is well known to those skilled in the art for comparative example 4, reduce the granularity of insoluble drug, increase its specific surface area
Its dissolution rate can be improved, but, for folic acid, in comparative example 4 folic acid granularity in 200 mesh hereinafter, not generate improve it is molten
Out-degree as a result, showing a degree of decline instead.
Test case 6
Preparation dissolution test:
According to the dissolution test method under Couteat of Folic Acid item in 2010 addendum of Chinese Pharmacopoeia, the present inventor also into
Go the dissolution test of folic acid solid pharmaceutical preparation obtained by embodiment 1-6, as a result such as the following table 8:
8. embodiment 1-6 of table and comparative example 3-5 Couteat of Folic Acid dissolution test result
| Dissolution rate | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| 30 minutes | 90.3% | 92.2% | 88.7% | 89.6% | 90.5% | 91.4% |
In synthesis known to 8 interpretation of result of table: each folic acid solid pharmaceutical preparation, 30 minutes dissolution rates obtained by embodiment 1-6 exist
85% or more.
Test case 7
Referring to the method in existing " chemicals stability study technological guidance principle " and condition is investigated, according to middle traditional Chinese medicines
Content, related substance, 30 minutes dissolution test methods in 2010 addendum of allusion quotation under Couteat of Folic Acid item, carry out embodiment 7,8 and
Steadiness under comparative example 1,2 gained Couteat of Folic Acid acceleration environments is investigated, as a result such as the following table 9:
9. embodiment 7,8 of table and comparative example 1,2 Couteat of Folic Acid accelerated stability results
In synthesis known to 9 interpretation of result of table: 1) embodiment 7,86 months under acceleration conditions, folate content, pteroic acid impurity
And dissolution rate shows good stability；2) Couteat of Folic Acid obtained by comparative example 1 and comparative example 2 wet granulation technology, content,
In terms of pteroic acid impurity and dissolution rate, obvious unstable situation is all had in 6 months, by taking comparison 1 as an example, 6 months in terms of content
4.9% (97.5%-92.6%) is inside had dropped, increases to 0.92% from 0.58% in pteroic acid impurity 6 months, dissolution rate 6 months
Inside have dropped 9.8% (83.2%-73.4%).
Test case 8
Referring to the method in " chemicals stability study technological guidance principle " and condition is investigated, according to Chinese Pharmacopoeia
Content, related substance, dissolution test method in 2010 addendums under Couteat of Folic Acid item, the present inventor have also carried out reality
The steadiness applied under Couteat of Folic Acid acceleration environment obtained by a 1-6 and comparative example 3-5 is investigated, as a result such as the following table 10:
10. embodiment 1-6 of table and comparative example 3-5 Couteat of Folic Acid accelerated stability result
10 interpretation of result of table in synthesis is it is found that embodiment 1-6 and comparative example 3-5 are to be related to or apply in technical process
Organic solvent or water, gained foliamin show good stability in 6 months.
Test case 9
It selects Beagle dog as animal subject, studies folic acid prepared by embodiment 7,8 of the present invention and comparative example 1-5
The bioavilability situation of piece needs predeclared to be the implementation of following testing programs Beagle dog in whole cycle
Raising 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 11 for the Beagle dog bioavailability study that test case of the present invention carries out:
11. embodiment 7,8 of table and comparative example 3-5 bioavailability study result
In synthesis known to 11 interpretation of result of table: 1) implementation that folic acid solid pharmaceutical preparation of the present invention and preparation method thereof obtains
Example 7,8 Couteat of Folic Acid, faster, show as Tmax is 45 minutes to infiltration rate, and comparative example 1,2 uses identical prescription through wet process system
The Couteat of Folic Acid Tmax of grain technique preparation is 1 hour；2) embodiment 7, the bioavilability of 8 gained Couteat of Folic Acid are apparently higher than comparative example
1 and 2, (105.3-74.6)/74.6=41.2%, 8 relative contrast's example 2 of embodiment are improved for 7 relative contrast's example 1 of embodiment
For improve (108.5-77.0)/77.0=40.9%；3) in folic acid solid pharmaceutical preparation of the present invention the granularity of folic acid to life
Object availability has significant effect: folic acid used in embodiment 7 is 90% or more size distribution in 100-150 mesh, with 3 institute of comparative example
(105.3-63.7)/63.7=65.3% is improved compared to bioavilability with the folic acid being distributed below 60 mesh granularities；8 institute of embodiment
It is folic acid biological availability phase of 90% or more the size distribution in 100-150 mesh, with size distribution used in comparative example 4,5 with folic acid
Than (108.5-94.0)/94.0=15.4% is respectively increased, (108.5-85.7)/85.7=26.6%；5) further comparison is real
It applies example 8 and comparative example 4 is found, although the granularity (crossing 200 meshes) of folic acid used in comparative example 4 is smaller compared with embodiment 8, make us frightened
It is odd, the smaller bioavilability of insoluble drug granularity for but producing and being generally considered to is higher run counter to as a result, implementing
15.4% is improved instead for the bioavilability relative contrast example 4 of 8 Couteat of Folic Acid of example, this is very inspirer.
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 (5)
1. a kind of folic acid solid pharmaceutical preparation, which is characterized in that be prepared by the following method:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and by starch, cream
Sugar, that magnesium stearate crosses 120 meshes is spare;
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed;
3) folic acid of the recipe quantity after step 1) processing is weighed to be uniformly mixed with step 2) resulting material using equivalent gradually-increased;
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0. 5-1. 5Mpa pressure, screening is received
Collect particle of the granularity within the scope of 24-65 mesh;
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix is pressed after 10-30 minutes
Piece is to get the Couteat of Folic Acid；
The tablet formulation are as follows: folic acid 4.0g, starch 1050g, lactose 2000g, magnesium stearate 50g.
2. a kind of folic acid solid pharmaceutical preparation, which is characterized in that be prepared by the following method:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and by starch, cream
Sugar, that magnesium stearate crosses 120 meshes is spare;
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed;
3) folic acid of the recipe quantity after step 1) processing is weighed to be uniformly mixed with step 2) resulting material using equivalent gradually-increased;
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0. 5-1. 5Mpa pressure, screening is received
Collect particle of the granularity within the scope of 24-65 mesh;
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix is pressed after 10-30 minutes
Piece is to get the Couteat of Folic Acid；
The prescription of the tablet are as follows: folic acid 50g, starch 1050g, lactose 2000g, magnesium stearate 50g.
3. folic acid solid pharmaceutical preparation according to claim 1 or claim 2, which is characterized in that the size distribution of the folic acid is in 100-150
Within the scope of mesh.
4. folic acid solid pharmaceutical preparation according to claim 1 or claim 2, which is characterized in that the dry granulation tablet forming technique preparation
Tablet, 30 minutes dissolution rates are not less than 85%.
5. the preparation method of folic acid solid pharmaceutical preparation as claimed in claim 1 or 2, which is characterized in that the tablet can be by following dry method
Pelletizing press sheet technique is prepared:
1) folic acid is sieved after airflow milling crushes 90% or more size distribution 100-150 mesh folic acid, and by starch, cream
Sugar, that magnesium stearate crosses 120 meshes is spare;
2) starch, lactose of the recipe quantity after step 1) processing is weighed to be uniformly mixed;
3) folic acid of the recipe quantity after step 1) processing is weighed to be uniformly mixed with step 2) resulting material using equivalent gradually-increased;
4) uniform mixed material obtained by step 3) through dry press dry-pressing and is crushed under 0. 5-1. 5Mpa pressure, screening is received
Collect particle of the granularity within the scope of 24-65 mesh;
5) particle obtained by step 4) is added to the magnesium stearate after step 1) processing of recipe quantity, total mix is pressed after 10-30 minutes
Piece is to get the Couteat of Folic Acid.
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| CN112336692A (en) * | 2020-12-02 | 2021-02-09 | 天津力生制药股份有限公司 | Folic acid tablet and preparation method thereof |
| CN113440499B (en) * | 2021-06-18 | 2022-04-22 | 北京斯利安药业有限公司 | Folic acid oral dissolving film agent and preparation method thereof |
| CN114404375B (en) * | 2022-01-21 | 2023-06-27 | 武汉九珑人福药业有限责任公司 | Folic acid solid preparation and raw material composition, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186664A (en) * | 1997-11-13 | 1998-07-08 | 北京医科大学实验药厂 | Folic acid supplementing agent for preventing neural tube deformity |
| CN101103985A (en) * | 2006-07-14 | 2008-01-16 | 北京华安佛医药研究中心有限公司 | Folic acid dropping pill and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186664A (en) * | 1997-11-13 | 1998-07-08 | 北京医科大学实验药厂 | Folic acid supplementing agent for preventing neural tube deformity |
| CN101103985A (en) * | 2006-07-14 | 2008-01-16 | 北京华安佛医药研究中心有限公司 | Folic acid dropping pill and its preparation method |
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