CN105496941A - Folic acid solid preparation and preparation method thereof - Google Patents
Folic acid solid preparation and preparation method thereof Download PDFInfo
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- CN105496941A CN105496941A CN201410499518.4A CN201410499518A CN105496941A CN 105496941 A CN105496941 A CN 105496941A CN 201410499518 A CN201410499518 A CN 201410499518A CN 105496941 A CN105496941 A CN 105496941A
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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 361
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 184
- 239000011724 folic acid Substances 0.000 title claims abstract description 184
- 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 179
- 229960000304 folic acid Drugs 0.000 title claims abstract description 179
- 238000002360 preparation method Methods 0.000 title claims abstract description 131
- 239000007787 solid Substances 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 72
- 238000009826 distribution Methods 0.000 claims abstract description 33
- 238000004090 dissolution Methods 0.000 claims abstract description 23
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 96
- 235000019359 magnesium stearate Nutrition 0.000 claims description 48
- 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 45
- 239000008101 lactose Substances 0.000 claims description 45
- 229920002472 Starch Polymers 0.000 claims description 42
- 239000008107 starch Substances 0.000 claims description 42
- 235000019698 starch Nutrition 0.000 claims description 42
- 239000002245 particle Substances 0.000 claims description 39
- 239000000463 material Substances 0.000 claims description 35
- 238000012545 processing Methods 0.000 claims description 32
- 239000008187 granular material Substances 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 31
- 238000007908 dry granulation Methods 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 18
- 238000003801 milling Methods 0.000 claims description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
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- 238000012216 screening Methods 0.000 claims description 15
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- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 239000002671 adjuvant Substances 0.000 claims description 11
- 238000003825 pressing Methods 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 10
- 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 claims description 8
- 239000002775 capsule Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 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 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 229940080428 lactose 200 mg Drugs 0.000 claims description 4
- 229940019142 folic acid 5 mg Drugs 0.000 claims description 2
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- 235000019580 granularity Nutrition 0.000 description 22
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- 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 18
- 238000000926 separation method Methods 0.000 description 17
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- 238000007922 dissolution test Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 6
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- 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 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 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
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
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- 230000003064 anti-oxidating effect Effects 0.000 description 1
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- 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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- 125000003929 folic acid group Chemical group 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medical technologies, in particular to a folic acid solid preparation and a preparation method thereof. The folic acid solid preparation is prepared from folic acid and pharmaceutically acceptable excipients by an appropriate process. More than 90% of the folic acid granularity is in a distribution range of 80-200 meshes. A unit preparation of the folic acid solid preparation contains 0.20-30.0mg of folic acid, and the balance pharmaceutically acceptable excipients. The folic acid with the granularity distribution and the pharmaceutically acceptable excipients are made into the folic acid solid preparation by an appropriate process, with a 30min dissolution rate of not less than 85%, the folic acid solid preparation not only has the clinical advantages of safety, effectiveness and controllable quality, but also has the comprehensive advantages of low energy consumption, environmental friendliness, and easy realization of industrialization.
Description
Technical field
The present invention relates to medical art, particularly relate to a kind of folic acid solid preparation and preparation method thereof.
Background technology
Folic acid (FolicAcid) belongs to vitamin B group; also known as vitamin(e) M, folic acid, FA; chemistry N-[4-[(2-amino-4-oxo-1 by name; 4-dihydro-6-pteridine) methylamino] benzoyl]-Pidolidone; usual title pteroylglutamic acid, molecular formula is C
19h
19n
7o
8(structural formula as shown in the formula), molecular weight 441.4, fusing point 250 DEG C, water-soluble (dissolubility is about 0.0016mg/mL) and most of organic solvent, can be dissolved in diluted acid and alkaline solution hardly.
The clinical practice historical origin of folic acid for a long time, Yang Yuzhu, Crown Prince's inflammation etc. outlined it and find applicating history in " progress of folic acid " literary composition: as far back as 1931, namely doctor doctor LucyWills of Bombay,India maternity hospital finds, yeast or liver extract can improve the megaloblastic anemia of women, therefore think in these extracts containing certain antianemia factor; Nineteen thirty-five, there is people in yeast and liver concentrate, find the factor of anti-monkey anemia; Nineteen thirty-nine the anti-chicken anemia that had again people to find in liver the factor; Nineteen forty-one, the people such as American scholar Mitchell have found a somatomedin of streptococcus acidi lactici in Herba Spinaciae, because being mainly derived from leaves of plants, therefore called after folic acid; 1945, the people such as Angier found when synthesizing pteroylglutamic acid, and above-mentioned discovery is same material, completes the mensuration of folic acid structure simultaneously.
Along with the development of clinical medicine and modern science, folic acid obtains more deeply applying widely in clinical practice, particularly in the prevention and therapy of prevention neonate neural tube defects, megaloblastic anemia, embody definite curative effect and advantage, create positive clinical effectiveness and social benefit widely; Simultaneously, modern medicine scientific research shows that folic acid also has good effect in reduction homocysteine, homocysteine is defined as the independent risk factor of cardiovascular and cerebrovascular disease usually by medical circle, therefore, increasing research focuses on the application of folic acid in cardiovascular and cerebrovascular disease field, and the evidence now accumulated display folic acid has stem-winding prospect in cardiovascular and cerebrovascular disease; Current, the potential medical value of folic acid also is constantly being found to realize, such as it also embodies certain clinical effect at antioxidation, anti-tumor aspect.
The clinical immense value of folic acid is undeniable and queries, but, as everyone knows, the embodiment that clinical drug is worth not only by active component decision itself, also with its administration, dosage form even production technology have close relationship.At present, folic acid main form of medication is clinically oral solid tablet, the main manufacturer of domestic commercially available folic acid comprises Beijing Scrianen Pharmaceutical Co., Ltd., Shenyang Gelin Pharmaceutical Co., Ltd., Huabei Pharmaceutic Co., Ltd, Jiangxi Pharmaceutical Co. Ltd. etc., dosage form is oral solid tablet, specification comprises 0.4mg and 5.0mg, belong to generally acknowledged small dimension preparation, specify by existing Chinese Pharmacopoeia, need the inspection carrying out its uniformity of dosage units, meanwhile, existing Chinese Pharmacopoeia also specifies the impurity and the dissolution test that carry out its preparation.The formulation of a clinical medicine quality standard and bound requirements carry out based on the feature of medicine itself, such as physicochemical property and biological property etc.According to the architectural feature of existing research and folic acid, analyzing known folic acid is a kind of chemical substance light, heat and wet (being embodied as water) and organic solvent (such as methanol, ethanol) etc. all being shown as to extreme difference stability; Current commercially available YESUAN PIAN is small dimension preparation, generally, small dimension preparation adopts non-wet granulation technology not easily mix homogeneously, therefore, current commercially available YESUAN PIAN all adopts the technique of wet granulation to prepare foliamin, inevitably applies water or organic solvent, be inevitably exposed to again the environment of heat in particle drying procedures under, bring huge safety risks to technical process and final preparation and clinical practice, do not meet the requirement that current Quality comes from advanced design theory; Simultaneously, in biological property, because of the feature of the low dissolving hypotonicity of folic acid, determine its objective fact that bioavailability is relatively low in vivo (medically it has been generally acknowledged that bioavailability is the direct determiner of clinical drug curative effect), finally, in the low body of folic acid, bioavailability causes the limitation that its clinical efficacy can not be not fully exerted further.
" a kind of YESUAN PIAN and preparation method thereof " (application number: prepare folic acid wet granular using 60% ethanol as the wet granulation technology of binding agent in patent 201110280578.3) of Shenyang Gelin Pharmaceutical Co., Ltd.'s application, then dryly granule must be done at 55-65 DEG C, further tabletted, obtains and has good uniformity of dosage units and the YESUAN PIAN of dissolution; But the impurity of undeclared YESUAN PIAN and bioavailability situation, analyze known in patent, 60% ethanol and temperature 55-65 DEG C are two key factors affecting folic acid stability, and this is very disadvantageous for the impurity controlling product; In addition, point out in patent that the dissolution of gained YESUAN PIAN is all more than 95%, but, for the medicine of this kind of low dissolving hypotonicity of folic acid, In vitro-in vivo correlation is often poor, external dissolution definitely can not point out the situation of bioavailability in body, and end reaction is on clinical efficacy.
" folic acid dropping pill and preparation method thereof " (application number: 200610099026.1) of Hua'anfo Medicine Research Center Co., Ltd., Beijing's application, " a kind of folic acid effervescent tablet and preparation method thereof " (application number: 200710107195.X) of Guangdong Shixin Pharmaceutical Co., Ltd.'s application, " a kind of folic acid pellet and preparation method thereof " (application number: 200810182808.0) of Tianjin Fulande Medical Science & Technology Development Co., Ltd.'s application, " folic acid enteric preparation composition and preparation method thereof " (application number: 200810117696.0) of Beijing Ruiyiren Science and Technology Development Co., Ltd.'s application, in technical process, all inevitably employ the condition affecting folic acid stability, comprise ethanol, high temperature in water and particle drying procedures, the risk that cannot evade is brought to product.
As everyone knows, medicine desirable clinically should be safe, effective, quality controllable, and the risk of safety is mainly caused by impurity, the embodiment of effectiveness depends primarily on the galenic pharmacy feature of medicine itself and medicine, and quality controllability is then that the technological design prepared by medicine and technical process determine.In summary, there is no effective technological means at present for providing a kind of folic acid medicine having more advantage clinically, therefore, it is current that in the urgent need to providing one to have, impurity is few, safety is high, bioavailability is high, effectiveness is good, the desirable folic acid pharmaceutical preparation of the clinical advantage such as stable technical process, repeatability are good, quality controllable, should meet less energy consumption, environmental friendliness simultaneously and be easy to the comprehensive advantage of realization of industrialization.
Summary of the invention
In order to solve the problem, the object of the present invention is to provide a kind of folic acid solid preparation and preparation method thereof.
For solving the problems of the technologies described above, the present invention by the following technical solutions, a kind of folic acid solid preparation.
Described solid preparation is processed by the folic acid of more than 90% particle size distribution within the scope of 80-200 order and pharmaceutically acceptable adjuvant to be prepared from;
Preferably, the particle size distribution of described folic acid is more than 90% within the scope of 100-150 order.
Containing folic acid 0.20-30.0mg in described folic acid solid preparation unit formulation;
Preferably, folic acid 0.40-10.0mg is contained in described folic acid solid preparation unit formulation.
Described pharmaceutically acceptable adjuvant comprises one or more compositionss in starch, pregelatinized Starch, microcrystalline Cellulose, lactose, hypromellose, polyvidone, sodium carboxymethyl cellulose, polyvidone, magnesium stearate, Pulvis Talci, correctives;
Preferably, described pharmaceutically acceptable adjuvant comprises one or more compositionss in starch, lactose, magnesium stearate.
Solid preparation of the present invention is including, but not limited to tablet, capsule, granule, dry suspension.
Preferably, described solid preparation is tablet.
Tablet of the present invention can be processed and is prepared from by powder vertical compression technique, dry granulation tablet forming technique.
Preferably, described tablet is processed by dry granulation tablet forming technique and is prepared from.
Tablet prepared by dry granulation tablet forming technique of the present invention, the dissolution of 30 minutes is not less than 85%.
Preferably, tablet of the present invention can be made up of following unit formulation prescription and is prepared from:
Folic acid 0.40mg, starch 105mg, lactose 200mg, magnesium stearate 5.00mg.
Preferably, described tablet can be made up of following unit formulation prescription and is prepared from:
Folic acid 5mg, starch 100mg, lactose 200mg, magnesium stearate 5.00mg.Tablet of the present invention can be prepared from by following dry granulation tablet forming technique:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed tabletting after 10-30 minute, obtains described YESUAN PIAN.
Adopt the folic acid solid preparation of the present invention that technique scheme obtains, the object that generation the present invention that can be desirable will reach and technique effect, specifically, a kind of folic acid solid preparation of the present invention and preparation method thereof can produce: 1) gained folic acid solid preparation impurity is few, and safety is high; 2) dissolution and bioavailability is high, Clinical efficacy is good; 3) stable technical process, quality reproduction is good, quality controllable Advantageous Effects; Further, a kind of folic acid solid preparation of the present invention and preparation method thereof, also has less energy consumption, environmental friendliness, is easy to industrialization and amplifies implementation trade-off advantage.
It should be noted that, at this, in order to the understanding summary of the invention of the present invention that enables technical field personnel of the present invention clearly errorless and technical connotation, the technical term that the present inventor relates to described, symbol, the reagent consumptive material be applied to and instrument and equipment do following explanation:
" order ": refer to the granularity measurement unit stated in Chinese Pharmacopoeia 2010 editions;
" instrument and equipment ": be commercially available routine instrument device without special instruction;
" adjuvant reagent ": be commercially available conventional reagent consumptive material without special instruction;
" unit formulation ": the per unit preparation referring to described folic acid solid preparation, such as, refer to 1 for tablet, and capsule refers to 1, and granule, dry suspension refer to 1 bag;
" correctives ": refer to the pharmaceutically acceptable material for improving mouthfeel, comprise sweeting agent, essence etc., be not limited to a certain or a certain classification, its consumption is to produce for the purpose of the acceptable mouthfeel of patient, the personnel of technical field of the present invention, by simply testing trial, can determine kind and the consumption of correctives;
" more than 90% particle size distribution is at 80-200 order ": refer to that the granularity of powder or granule has more than 90% within the scope of 80-200 object, also can be understood as powder beyond 80-200 order or granule below 10%;
" Tmax ": time when medicine reaches maximum plasma concentration after showing medicine;
" Cmax ": the maximum plasma concentration detected in body after showing medicine;
" AUC
0 ~ ∞": refer to lower area of blood concentration-time curve; in bioavailability study process; under the prerequisite that dosage is identical; this numerical value height then illustrates that bioavailability is high; this numerical value low explanation bioavailability is low; need to further illustrate, the height of bioavailability of the present invention adopts the height of this numerical value to represent.
Detailed description of the invention
In order to understand the present invention further, below in conjunction with embodiment, the present invention is described in detail.
Folic acid solid preparation provided by the invention and preparation method thereof, the folic acid adopted in the prescription of described folic acid solid preparation is the folic acid of specified particle size distribution, and what described preparation method adopted is the technique not relating to heat, water or organic solvent in technical process.
Folic acid raw material in folic acid solid preparation prescription of the present invention is crush and screen through airflow milling the folic acid of more than 90% particle size distribution within the scope of 80-200 order obtained, and according to the difference of raw material granularity, by the Task-size Controlling of adjuvant in specific scope, thus solve and well known to a person skilled in the art that small dimension preparation adopts the insoluble technical barrier of non-wet granulation technology.For following embodiment 7, unit formulation part Folic Acid is only 0.4mg, belong to the preparation of minimum specification, uniformity of dosage units problem is extremely difficult to resolve certainly, the present inventor is after a large amount of creative works, find when employing more than 90% particle size distribution prepares YESUAN PIAN at 100-150 object folic acid raw material, by used adjuvant lactose, starch, dolomol by 120 mesh sieves, the problem of uniformity of dosage units can be solved; The present inventor also once attempted the problem granularity of lactose, starch, magnesium stearate being crossed 80 mesh sieves or 150 mesh sieves solution uniformity of dosage units, but all created the result of cold people's disappointment; Therefore, it should be noted that, in order to solve the problem of uniformity of dosage units, the granularity of raw material and the control of adjuvant granularity are closely related, need under specific granularity condition coordinates, just can obtain the small dimension YESUAN PIAN that the uniformity of dosage units that adopts dry granulation process to prepare is qualified.
In addition, as everyone knows, folic acid is to heat, water and only extremely unstable, therefore, in the preparation method of folic acid solid preparation of the present invention, come from based on quality the theory of design preferred technique all effectively prevent appearance to folic acid unfavorable factor, efficiently solve the stability of technical process, improve the quality controllability of product, need at this it is emphasized that, as well known to those skilled in the art, distribution for insoluble drug raw material granularity has appreciable impact to bioavailability in preparation body, the present inventor have also discovered this phenomenon through the research of following each detailed description of the invention, result shows, preparation prepared by the folic acid in particle size distribution of the present invention has higher bioavailability, and the folic acid raw material departed from this particle size distribution creates the fact that declined bioavailability of oral administration is reduced levels, simultaneously, after a large amount of performing creative labour, the present inventor surprisingly finds, in folic acid solid preparation body of the present invention, bioavailability is not only by the impact of folic acid raw material granularity distribution, and its preparation technology and method also have bioavailability to be affected extremely significantly, such as embodiment 8 and comparative example 2 adopt identical formula preparation YESUAN PIAN, the particle size distribution of prescription Folic Acid and each adjuvant is also all consistent, but, can find in test case, the YESUAN PIAN that the bioavailability of the YESUAN PIAN that embodiment 8 of the present invention adopts dry granulation process to prepare adopts wet granulation technology to prepare apparently higher than comparative example 2, relative to comparative example 2, the bioavailability of embodiment 8 improves 40.9%, this be exceed completely the present inventor expect and infusive.
Below, the personnel for the ease of the technical field of the invention understand the present invention, the invention provides following detailed description of the invention and are described further described folic acid solid preparation and preparation method thereof:
Embodiment 1
The preparation of powder vertical compression technique YESUAN PIAN:
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 technology:
1) adopt airflow milling to pulverize appropriate folic acid raw material, the part of screening more than 90% particle size distribution within the scope of 80-120 order, keeps in Dark Place for subsequent use;
2) appropriate lactose, polyvidone, microcrystalline Cellulose, magnesium stearate are crossed 80 mesh sieves respectively, for subsequent use;
3) take 1 of recipe quantity) gained folic acid raw material and recipe quantity 2) gained PVP K30 mix homogeneously;
4) 2 of recipe quantity are taken) gained lactose and microcrystalline Cellulose mix homogeneously;
5) by 3) gained material and 4) after gained material adopts the equivalent method of progressively increasing to be mixed to 15% of prescription total amount, with 4 of surplus) gained material adds magnesium stearate after mixing homogeneously, and total mixed 20 minutes, obtains mixed uniformly intermediate;
6) with tablet machine, by 5) gained intermediate presses 315mg sheet weight sheet, obtains powder vertical compression YESUAN PIAN.
Embodiment 2
The preparation of folic acid dry suspension:
Preparation prescription:
| Supplementary material | Recipe quantity (10000 bags) |
| Folic acid | 100g |
| Starch | 1300g |
[0063]
| Lactose | 1400g |
| Correctives | 60.0g |
| Sodium carboxymethyl cellulose | 140g |
Preparation technology:
1) adopt airflow milling to pulverize appropriate folic acid raw material, the part of screening more than 90% particle size distribution within the scope of 120-150 order, keeps in Dark Place for subsequent use;
2) appropriate amount of starch, lactose, correctives, sodium carboxymethyl cellulose are crossed 100 mesh sieves respectively, for subsequent use;
3) take 1 of recipe quantity) gained folic acid raw material and recipe quantity 2) gained correctives equivalent progressively increases method mix homogeneously;
4) 2 of recipe quantity are taken) gained sodium carboxymethyl cellulose and 3) gained material mixs homogeneously;
5) by 4) gained material and recipe quantity 2) gained starch, lactose always mixed 15 minutes, obtain mixed uniformly intermediate;
6) by 5) gained intermediate divides by 300mg/ bag and is filled in aluminum-plastic composite membrane bag, obtains folic acid dry suspension.
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 |
| Pulvis Talci | 20.0g |
| Magnesium stearate | 40.0g |
| Microcrystalline Cellulose | 1400g |
| Hypromellose | 40.0g |
Preparation technology:
1) adopt airflow milling to pulverize appropriate folic acid raw material, the part of screening more than 90% particle size distribution within the scope of 100-120 order, keeps in Dark Place for subsequent use;
2) appropriate lactose, Pulvis Talci, magnesium stearate, microcrystalline Cellulose, hypromellose are crossed 100 mesh sieves respectively, for subsequent use;
3) take 2 of recipe quantity) gained Pulvis Talci, magnesium stearate mix homogeneously;
4) by 1 of recipe quantity) gained folic acid and 2) gained hypromellose adopts the equivalent method of progressively increasing to mix homogeneously, then with 2 of recipe quantity) gained lactose, microcrystalline Cellulose mix homogeneously;
5) by 4) gained material is through dry press dry-pressing and after pulverizing, screening 50-80 object granule, then with 3) gained material always mixes to evenly, packed in aluminum-plastic composite membrane bag by 310.2mg/, obtains 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 |
| Pulvis Talci | 20.0g |
| Magnesium stearate | 40.0g |
| Microcrystalline Cellulose | 1500g |
| Hypromellose | 30.0g |
Preparation technology:
1) adopt airflow milling to pulverize appropriate folic acid raw material, the part of screening more than 90% particle size distribution within the scope of 100-150 order, keeps in Dark Place for subsequent use;
2) appropriate lactose, Pulvis Talci, magnesium stearate, microcrystalline Cellulose, hypromellose are crossed 100 mesh sieves respectively, for subsequent use;
3) by 1 of recipe quantity) gained folic acid and 2) gained hypromellose adopts the equivalent method of progressively increasing to mix homogeneously, then with 2 of recipe quantity) gained lactose, microcrystalline Cellulose mix homogeneously;
4) by 3) gained material is through dry press dry-pressing and pulverize, after crossing 65 mesh sieves again with 2 of recipe quantity) gained Pulvis Talci, magnesium stearate always mix to evenly, press the grain weight filled capsules of 309.4mg, obtain folic acid capsule with capsule-filling agent.
Embodiment 5
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 300g |
| Magnesium stearate | 40.0g |
| Microcrystalline Cellulose | 1500g |
| Pregelatinized Starch | 1200g |
| Hypromellose | 60.0g |
[0094]preparation technology:
1) adopt airflow milling to pulverize appropriate folic acid raw material, the part of screening more than 90% particle size distribution within the scope of 150-200 order, keeps in Dark Place for subsequent use;
2) magnesium stearate, microcrystalline Cellulose, pregelatinized Starch, hypromellose will be fitted and cross 120 mesh sieves respectively, for subsequent use;
3) 1 of recipe quantity is taken) gained folic acid and 2 of recipe quantity) gained hypromellose mixs homogeneously;
4) by 2 of recipe quantity) gained microcrystalline Cellulose, pregelatinized Starch and 3) gained material mixs homogeneously;
5) by 4) gained material is through dry press dry-pressing and after pulverizing, screening 24-65 object granule;
6) 2 of recipe quantity are taken) gained magnesium stearate is added to 5) always mix to evenly in gained granule, press the heavy tabletted of 310mg sheet with tablet machine, obtain YESUAN PIAN.
Embodiment 6
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 100.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 10-20 minute, press 320mg sheet weight sheet, obtain described YESUAN PIAN.
Embodiment 7
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
[0115]
| Folic acid | 4.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 20-30 minute, press 310.4mg sheet weight sheet, obtain described YESUAN PIAN.
Embodiment 8
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 15-25 minute, press 315mg sheet weight sheet, obtain described YESUAN PIAN.
Comparative example 1
The preparation of wet granulation technology YESUAN PIAN:
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 technology:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) adopt the Starchy pulps solution rushing slurry processes preparation appropriate 10% as binding agent;
3) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
4) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
5) by step 4) gained homogeneous mixture of material for binding agent, prepares wet granular through oscillating granulator with 10% starch slurry;
6) by step 5) gained wet granular at 60 DEG C dry 2 hours, and the granule of screen size within the scope of 24-65 order;
7) by step 6) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 20-30 minute, press 310.4mg sheet weight sheet, obtain described YESUAN PIAN.
Comparative example 2
The preparation of wet granulation technology YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
| 3% hypromellose alcoholic solution | In right amount |
Preparation technology:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) be that the hypromellose cellulose solution of 3% is as binding agent with the ethanol compound concentration of 95%;
3) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
4) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
5) by step 4) gained homogeneous mixture of material for binding agent, prepares wet granular through oscillating granulator with 3% hypromellose cellulose solution;
6) by step 5) gained wet granular at 55 DEG C dry 1 hour, and the granule of screen size within the scope of 24-65 order;
7) by step 6) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 15-25 minute, press 315mg sheet weight sheet, obtain described YESUAN PIAN.
Comparative example 3
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 4.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is crossed 60 mesh sieves after airflow milling is pulverized, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 20-30 minute, press 310.4mg sheet weight sheet, obtain described YESUAN PIAN.
Comparative example 4
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is crossed 200 mesh sieves after airflow milling is pulverized, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 15-25 minute, press 315mg sheet weight sheet, obtain described YESUAN PIAN.
Comparative example 5
The preparation of dry granulation process YESUAN PIAN:
Preparation prescription:
| Supplementary material | Recipe quantity (10000) |
| Folic acid | 50.0g |
| Starch | 1050g |
| Lactose | 2000g |
| Magnesium stearate | 50.0g |
Preparation technology:
1) folic acid is sieved after airflow milling is pulverized more than 70% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed after 15-25 minute, press 315mg sheet weight sheet, obtain described YESUAN PIAN.
Before carrying out following test case 1 and 2, it should be noted that, intermediate described in test case 1 and 2 is defined as the material after always mixing in above-mentioned each preparation embodiment and preparation comparative example by the present inventor; It should be explained that in addition, in following each test case, described pteroic acid is a kind of known impurities of folic acid, described list is mixed the maximum single impurity referring to and detect in analytical test process, described total impurities refers to the total impurities comprising pteroic acid, single assorted and other impurity, and described Related substances separation refers to pteroic acid, single assorted and total assorted test-based examination.
Test case 1
Intermediate Related substances separation:
According to the Related substances separation method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, carry out the Related substances separation of intermediate in embodiment 7,8 and comparative example 1,2 technical process, result is as following table 1:
Table 1. embodiment 7,8 and comparative example 1,2 intermediate Related substances separation result
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Pteroic acid | 0.11％ | 0.13％ | 0.48％ | 0.35％ |
| Single assorted | 0.23％ | 0.22％ | 0.75％ | 0.54％ |
| Total assorted | 0.65％ | 0.68％ | 1.74％ | 1.37％ |
In comprehensive analysis, table 1 check result is known: 1) embodiment 7 of the present invention, embodiment 8 midbody particle that adopts the technique of dry granulation to prepare, the amount of pteroic acid, single assorted and total impurities is all significantly less than comparative example 1, midbody particle that comparative example 2 adopts the technique of wet granulation to prepare, in objective examination's the data obtained, every related substance of comparative example 1, comparative example 2 is all at more than 2 times of embodiment 7,8; 2) analyze further, comparative example 1 adopts 10% Starchy pulps solution to carry out wet granulation, comparative example 2 adopts the hypromellose alcoholic solution of 3% to carry out wet granulation, Related substances separation result shows the contact of organic solvent in preparation process and to relate to the impact of folic acid stability relative to water be less, but, compared with embodiment 7,8, the application of second alcohol and water all creates very adverse influence to the preparation process of preparation, shows as pteroic acid, single assorted, total assorted amount is all relatively high.As everyone knows, the height of its related substances directly determines quality and the clinical safety of product, and this objective fact that wet granulation technology process intermediates its related substances is high brings huge potential safety hazard to final preparation and clinical practice thereof.
Test case 2
Intermediate Related substances separation:
According to the Related substances separation method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the present inventor also carries out the Related substances separation of intermediate in embodiment 1-6 and comparative example 3-5 technical process, and result is as following table 2:
Table 2. embodiment 1-6 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 |
[0198]
| Pteroic acid | 0.17％ | 0.20％ | 0.19％ | 0.24％ | 0.17％ | 0.22％ | 0.24％ | 0.23％ | 0.24％ |
| Single assorted | 0.35％ | 0.36％ | 0.40％ | 0.42％ | 0.38％ | 0.45％ | 0.45％ | 0.48％ | 0.50％ |
| Total assorted | 0.87％ | 0.82％ | 0.86％ | 0.80％ | 0.78％ | 0.92％ | 0.95％ | 0.90％ | 0.93％ |
In comprehensive analysis each embodiment of table 2 and comparative example midbody particle Related substances separation result known: embodiment 1-6 and comparative example 3-5 does not all apply water or organic solvent in technical process, therefore, relatively good stability is all shown in each embodiment and preparation example technical process, pteroic acid, single assorted and total assorted level are all a lower level, pteroic acid is all below 0.25%, single assorted all not higher than 0.50%, total assorted all lower than 1.00%.
Test case 3
Preparation related substance and Content uniformity test:
According to the Related substances separation method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, carry out the Related substances separation of embodiment 7,8 and comparative example 1,2 gained YESUAN PIAN, result is as following table 3:
Table 3. embodiment 7,8 and comparative example 1,2 YESUAN PIAN Related substances separation result
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Pteroic acid | 0.14％ | 0.15％ | 0.58％ | 0.46％ |
| Single assorted | 0.26％ | 0.23％ | 0.94％ | 0.83％ |
| Total assorted | 0.73％ | 0.75％ | 1.87％ | 1.65％ |
The result comprehensively going up table 1 in table 3 and test case 1 is known: 1) comparative example 1,2 is after being prepared into whole finished dosage form by midbody particle processing, pteroic acid, single assorted, total assorted rising all had to a certain degree, this is owing to containing the water or organic solvent do not removed completely in intermediate, at tableting processes because violent mechanical condition produces a large amount of heat, and folic acid occurs that degraded causes under the condition of suitable quantity of water or organic solvent exposure; 2) analyze further, embodiment 7,8 is after midbody particle processing is prepared into whole finished dosage form, and significant change does not appear in pteroic acid, single assorted, total mixing, and shows good technology stability; 3) by embodiment 7,8 and comparative example 1,2 relative analysis, pteroic acid, the list of the whole finished dosage form of embodiment 7,8 are assorted, total assorted all obviously lower, specifically, all in comparative example 1,2 less than 1/2, in this and technical process, the Control of Impurities of midbody particle is all right is closely related, in other words, illustrating that the impact of technical process on final preparation is very significantly, is the necessity with practical significance to the quality control of product.
According to the Content uniformity test method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, carry out the Content uniformity test of embodiment 7,8 and comparative example 1,2 YESUAN PIAN, result is as following table 4:
Table 4. embodiment 7,8 and comparative example 1,2 YESUAN PIAN Content uniformity test result
| Embodiment 7 | Embodiment 8 | Comparative example 1 | Comparative example 2 | |
| Average content X | 98.5 | 98.3 | 97.5 | 98.0 |
[0209]
| 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 |
Comprehensive upper table 4 interpretation of result is known: under the condition of folic acid specified particle size distribution of the present invention, and suitably control the grain size characteristic of adjuvant, adopt the embodiment of the present invention 7,8 gained YESUAN PIAN prepared by dry granulation, all there is good uniformity of dosage units, result, much smaller than the requirement of A+1.80S≤15 of States Pharmacopoeia specifications, is slightly better than the YESUAN PIAN of comparative example 1,2 employing prepared by wet granulation simultaneously.
Test case 4
Preparation related substance and Content uniformity test:
According to the Related substances separation method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the present inventor has also carried out the Related substances separation of embodiment 1-6 and comparative example 3-5 gained YESUAN PIAN, and result is as following table 5:
Table 5. embodiment 1-6 and comparative example 3-5 YESUAN PIAN 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％ |
| Single assorted | 0.37％ | 0.39％ | 0.42％ | 0.45％ | 0.40％ | 0.47％ | 0.48％ | 0.51％ | 0.53％ |
| Total assorted | 0.89％ | 0.86％ | 0.90％ | 0.85％ | 0.81％ | 0.96％ | 0.98％ | 0.94％ | 0.97％ |
In comprehensive upper table 5 and test case 3, the result of table 3 is known: embodiment 1-6 and comparative example 3-5 processed by midbody particle be prepared into whole finished dosage form after pteroic acid, singly assortedly, total assortedly to have no significant change, show good technology stability.
According to the Content uniformity test method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the present inventor has also carried out the Content uniformity test of embodiment 1-6 and comparative example 3-5 folic acid solid preparation, and result is as following table 6:
Table 6. embodiment 1-6 and comparative example 3-5 YESUAN PIAN Content uniformity test result
Comprehensive upper table 6 interpretation of result is known: embodiment 1-6 and comparative example 3,5 all have good uniformity of dosage units, and result is 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 Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, carry out the dissolution test of embodiment 7,8 and comparative example 1-5 gained YESUAN PIAN, result is as following table 7:
Table 7. embodiment 7,8 and comparative example 1,2 YESUAN PIAN dissolution test result
| Dissolution | 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％ |
Comprehensive upper table 7 interpretation of result is known: 1) dissolution of embodiment 7, embodiment 8 gained YESUAN PIAN is all more than 90%, has higher dissolution, and prompting simultaneously may have bioavailability in excellent body; Analyze comparative example 7,8 and comparative example 1,2 YESUAN PIAN dissolution results known, the 30 minutes dissolutions adopting dry granulation gained YESUAN PIAN all higher than wet granulation comparative example 1,2 YESUAN PIAN dissolution more than 10%; 2) analyze comparative example 7,8 and comparative example 3,4,5 YESUAN PIAN dissolution results known, the dissolution of particle size and its distribution on folic acid solid preparation of folic acid raw material has to be affected significantly, and the present inventor surprisingly finds that the folic acid only in particle size range of the present invention has best dissolution; 3) it should be noted that, for comparative example 4, as well known to those skilled in the art, reduce the granularity of insoluble drug, increase its specific surface area and can improve its dissolution, but, for folic acid, comparative example 4 Folic Acid granularity, below 200 orders, does not produce the result improving dissolution, shows decline to a certain degree on the contrary.
Test case 6
Preparation dissolution test:
According to the dissolution test method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the present inventor has also carried out the dissolution test of embodiment 1-6 gained folic acid solid preparation, and result is as following table 8:
Table 8. embodiment 1-6 and comparative example 3-5 YESUAN PIAN dissolution test result
| Dissolution | 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％ |
Comprehensive upper table 8 interpretation of result is known: each folic acid solid preparation of embodiment 1-6 gained, the dissolution of 30 minutes is all more than 85%.
Test case 7
With reference to the method in existing " chemicals stability study technological guidance principle " and the condition of investigation, according to content, related substance, 30 minutes dissolution test methods under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the steadiness carried out under embodiment 7,8 and comparative example 1,2 gained YESUAN PIAN acceleration environment is investigated, and result is as following table 9:
Table 9. embodiment 7,8 and comparative example 1,2 YESUAN PIAN accelerated stability result
Comprehensive upper table 9 interpretation of result is known: 1) embodiment 7,86 months under acceleration conditions, and folate content, pteroic acid impurity and dissolution all show good stability; 2) comparative example 1 and comparative example 2 wet granulation technology gained YESUAN PIAN, in content, pteroic acid impurity and dissolution, all there is in 6 months obviously unstable situation, to contrast 1, content aspect have dropped 4.9% (97.5%-92.6%) in 6 months, pteroic acid impurity was increased to 0.92% from 0.58% in 6 months, and dissolution have dropped 9.8% (83.2%-73.4%) in 6 months.
Test case 8
With reference to the method in " chemicals stability study technological guidance principle " and the condition of investigation, according to content, related substance, dissolution test method under Chinese Pharmacopoeia 2010 addendum Folic Acid sheet item, the steadiness that the present inventor has also carried out under embodiment 1-6 and comparative example 3-5 gained YESUAN PIAN acceleration environment is investigated, and result is as following table 10:
Table 10. embodiment 1-6 and comparative example 3-5 YESUAN PIAN accelerated stability result
Comprehensive upper table 10 interpretation of result is known, and embodiment 1-6 and comparative example 3-5 is and relates to or apply organic solvent or water in technical process, and gained foliamin showed good stability in 6 months.
Test case 9
Select Beagle dog as animal subject, study the bioavailability situation of YESUAN PIAN prepared by embodiment 7,8 of the present invention and comparative example 1-5, need predeclaredly be, the raising of enforcement Beagle dog within the whole cycle of following testing program all adopts same standardized diet, to get rid of the adverse effect that food may bring result.
Animal subject is selected and grouping: select Beagle dog female, healthy, of the same age, and body weight, all within the scope of 10 ± 1.0kg, amounts to 42, is divided into 7 groups at random, often organizes 6;
Testing program: 1) test and do not use any medicine in first 21 days; 2) test first 7 days, the medicine giving 0.1mg folic acid/kg body weight every day carries out the presaturation of each animal subject background, makes the background folic acid concentration of each animal subject reach the level of stable state; 3) test first 1 day 20:00 respectively to organize animal subject and start fasting, test 7:00 on the same day gives the medicine of 0.5mg folic acid/kg body weight on an empty stomach, 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), extract forelimb median vein 2mL blood and keep sample; 4) sample of commercially available Beagle dog folic acid ELISA kit to each sampling time point of each tested treated animal is adopted to carry out folate content detection, and calculate the average of each tested group 6 each assessment items of Beagle dog, here it is to be noted before sample analysis detects, the precision, the response rate, specificity, detectability etc. of the present inventor to the method have carried out the Method validation of system, result shows, this analytical method is that science is feasible.
The result of the Beagle dog bioavailability study adopting test case of the present invention to carry out is as following table 11:
Table 11. embodiment 7,8 and comparative example 3-5 bioavailability study result
Comprehensive upper table 11 interpretation of result is known: 1) embodiment 7,8 YESUAN PIAN of folic acid solid preparation of the present invention and preparation method thereof acquisition, infiltration rate is faster, showing as Tmax is 45 minutes, and comparative example 1,2 adopts identical prescription to be 1 hour through YESUAN PIAN Tmax prepared by wet granulation technology; 2) bioavailability of embodiment 7,8 gained YESUAN PIAN is apparently higher than comparative example 1 and 2, embodiment 7 relative contrast example 1 improves (105.3-74.6)/74.6=41.2%, and embodiment 8 relative contrast example 2 improves (108.5-77.0)/77.0=40.9%; 3) granularity of folic acid solid preparation Folic Acid of the present invention has great impact to bioavailability: embodiment 7 folic acid used be more than 90% particle size distribution at 100-150 order, bioavailability improves (105.3-63.7)/63.7=65.3% compared with the folic acid distributed below comparative example 3 60 order granularities used; Embodiment 8 folic acid used is that more than 90% particle size distribution is at 100-150 order, (108.5-94.0)/94.0=15.4% is improved respectively, (108.5-85.7)/85.7=26.6% compared with the folic acid biological availability of comparative example 4,5 particle size distribution used; 5) comparative example 8 and comparative example 4 find further, although the granularity of comparative example 4 folic acid used (crossing 200 mesh sieves) is less compared with embodiment 8, but surprisingly, but create and usual the thought insoluble drug granularity more higher result of runing counter to of atom availability, the bioavailability relative contrast example 4 of embodiment 8 YESUAN PIAN improves 15.4% on the contrary, and this is very inspirer.
The explanation of above embodiment just understands method of the present invention and core concept for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (10)
1. a folic acid solid preparation, solid preparation is processed by the folic acid of more than 90% particle size distribution within the scope of 80-200 order and pharmaceutically acceptable adjuvant to be prepared from.
2. folic acid solid preparation according to claim 1, it is characterized in that, the particle size distribution of described folic acid is within the scope of 100-150 order.
3. folic acid solid preparation according to claim 1, is characterized in that, containing folic acid 0.20-30.0mg in described solid preparation unit formulation.
4. folic acid solid preparation according to claim 1, it is characterized in that, described pharmaceutically acceptable adjuvant comprises one or more compositionss in starch, pregelatinized Starch, microcrystalline Cellulose, lactose, hypromellose, polyvidone, sodium carboxymethyl cellulose, polyvidone, magnesium stearate, Pulvis Talci, correctives.
5. folic acid solid preparation according to claim 1, it is characterized in that, described solid preparation can be tablet, capsule, granule, dry suspension.
6. folic acid solid preparation according to claim 5, is characterized in that, described tablet can be processed and is prepared from by powder vertical compression technique, dry granulation tablet forming technique.
7. folic acid solid preparation according to claim 6, it is characterized in that, tablet prepared by described dry granulation tablet forming technique, the dissolution of 30 minutes is not less than 85%.
8. folic acid solid preparation and preparation method thereof according to claim 5, is characterized in that, contain in the unit formulation of described tablet: folic acid 0.40mg, starch 105mg, lactose 200mg, magnesium stearate 5.00mg.
9. folic acid solid preparation and preparation method thereof according to claim 5, is characterized in that, contain in the unit formulation of described tablet: folic acid 5mg, starch 100mg, lactose 200mg, magnesium stearate 5.00mg.
10. the preparation method of folic acid solid preparation according to claim 8 or claim 9, it is characterized in that, described tablet can be prepared from by following dry granulation tablet forming technique:
1) folic acid is sieved after airflow milling is pulverized more than 90% particle size distribution at 100-150 object folic acid, and by starch, lactose, that magnesium stearate crosses 120 mesh sieves is for subsequent use;
2) take recipe quantity through step 1) processing after starch, lactose mix homogeneously;
3) recipe quantity is taken through step 1) folic acid after processing and step 2) gained material adopts the equivalent method of progressively increasing to mix homogeneously;
4) by step 3) gained uniform mixed material pulverizes through dry press dry-pressing under 0.5-1.5Mpa pressure, and the granule of granularity within the scope of 24-65 order is collected in screening;
5) by step 4) gained granule add recipe quantity through step 1) magnesium stearate after processing, total mixed tabletting after 10-30 minute, obtains described YESUAN PIAN.
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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 |
| CN113440499A (en) * | 2021-06-18 | 2021-09-28 | 北京斯利安药业有限公司 | Folic acid oral dissolving film agent and preparation method thereof |
| CN114404375A (en) * | 2022-01-21 | 2022-04-29 | 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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| CN111419816A (en) * | 2020-04-28 | 2020-07-17 | 广东润源中天生物科技有限公司 | Vitamin B tablets and production method thereof |
| 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 |
| CN113440499A (en) * | 2021-06-18 | 2021-09-28 | 北京斯利安药业有限公司 | Folic acid oral dissolving film agent and preparation method thereof |
| CN114404375A (en) * | 2022-01-21 | 2022-04-29 | 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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