CN113855641A - Preparation method of folic acid solid preparation - Google Patents
Preparation method of folic acid solid preparation Download PDFInfo
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- CN113855641A CN113855641A CN202111381919.6A CN202111381919A CN113855641A CN 113855641 A CN113855641 A CN 113855641A CN 202111381919 A CN202111381919 A CN 202111381919A CN 113855641 A CN113855641 A CN 113855641A
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- Prior art keywords
- folic acid
- preparation
- granules
- tablets
- excipient
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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 170
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 87
- 239000011724 folic acid Substances 0.000 title claims abstract description 87
- 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 83
- 229960000304 folic acid Drugs 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 239000007787 solid Substances 0.000 title claims abstract description 26
- 239000008187 granular material Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 21
- 239000003381 stabilizer Substances 0.000 claims abstract description 18
- 239000000314 lubricant Substances 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 238000002156 mixing Methods 0.000 claims description 18
- 229920000881 Modified starch Polymers 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 238000007873 sieving Methods 0.000 claims description 14
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- 235000012239 silicon dioxide Nutrition 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 10
- 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 8
- 239000008101 lactose Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 7
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 7
- 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 claims description 6
- 229920002261 Corn starch Polymers 0.000 claims description 5
- 235000021355 Stearic acid Nutrition 0.000 claims description 5
- 239000008120 corn starch Substances 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
- 239000008117 stearic acid Substances 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 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 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 235000001465 calcium Nutrition 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 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 3
- 206010016880 Folate deficiency Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 2
- 208000010188 Folic Acid Deficiency Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 231100001016 megaloblastic anemia Toxicity 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 235000021022 fresh fruits Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/4833—Encapsulating processes; Filling of capsules
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- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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Abstract
The invention provides a preparation method of a folic acid solid preparation; the tablet is prepared by active ingredient folic acid and other pharmaceutic adjuvants through proper process, the folic acid is crushed and sieved by a 200-mesh sieve, and is granulated with excipient and stabilizer, and the dried granules are added with lubricant and pressed into tablets with certain hardness or the granules are directly filled into capsules. The preparation method is easy for industrial production and the quality of the product is consistent; the folic acid solid preparation has excellent stability and uniformity.
Description
Technical Field
The invention relates to the technical field of antianemia drugs, in particular to a preparation method of a folic acid solid preparation.
Background
Folic acid is a B-group vitamin, consists of pteridine, p-aminobenzoic acid and L-glutamic acid, and is widely present in meat, fresh fruits and vegetables. In 1931, Wills et al, a doctor in the Indian Mumbay obstetrics Hospital, discovered that yeast or liver concentrates had some effect on megaloblastic anemia symptoms in pregnant women, and these extracts were thought to have some anti-anemia factor; in 1935, yeast and liver extracts were found to have some effect on the anemia symptoms of monkeys, which were described as VM; in 1939, a factor against chicken anemia was found in the liver, known as VBe; in 1941, h.k.mitchell et al found that spinach contains a factor of streptococcus lactis, called folate. In 1945, R.B. Angier et al, when synthesizing pteroylglutamic acid, found that all the above factors were the same substance and completed the structure determination, and they were often referred to as folic acid thereafter. Therefore, folic acid is also called vitamin B9, anti-anemia factor, pteroylglutamic acid, etc.
Clinical administration forms of folic acid include oral administration and injection, and corresponding dosage forms include powder, injection, tablets and the like; among them, tablets are most commonly available on the market. Folacin tablets were first developed by MERUS LABS LUXCO II S.A R.L. company, marketed in France in 1947 under the trade name SPECIAFOLDINE, with a specification of 5 mg; subsequently, 1mg, 5mg specification folic acid tablets were marketed in the United states and Japan one after the other; in 2003, 0.4mg sized folic acid tablets were marketed. Folic acid tablets as antianemia agents; used for folic acid deficiency caused by various reasons and megaloblastic anemia caused by folic acid deficiency; preventive administration for pregnant and lactating women; folate deficiency caused by chronic hemolytic anemia.
According to the reports of related documents, folic acid is easy to destroy in an acid solution, unstable to heat, easy to lose at room temperature and easy to destroy by visible light. Japanese orange peel book states: folic acid was degraded by about 10% (1.0 g/150 ml) in a pH6.8 dissolution medium under direct sunlight for 7 hours. Therefore, the folic acid has poor stability, and certain difficulty is brought to preparation of the preparation. First, we prepared a commercially available formulation folic acid tablet (SPECIAFOL)DINE®) The inspection shows that the stability of the preparation sold on the market is poor, and each impurity in related substances continuously grows along with the increase of the standing time at room temperature; the maximum single impurity in the related substances reaches 1.12 percent in the near effective period, and exceeds the limit (1.0 percent) of the single impurity in the related substances of folic acid tablets in the current Chinese pharmacopoeia.
The patent of Shenyang Gulin pharmaceutical Co., Ltd for "a folic acid tablet and its preparation method" (application number: 201110280578.3) adopts wet granulation process, folic acid and lactose are mixed according to equal amount by gradually adding method, then mixed with starch and sucrose uniformly, granulated by adding 60% ethanol, wet-sized with 30 mesh screen, put the prepared wet granules into a hot air circulation oven at 55-65 ℃ for material drying for 3.5-4.5 hours, dried and sized with 30 mesh screen, mixed with magnesium stearate for 30 minutes and tabletted. The folic acid tablets obtained in the patent have uniform content, the dissolution rate is over 95 percent, but the stability of the folic acid tablets is not described; analysis shows that folic acid is unstable at high temperature, wet particles are placed in a hot air circulation oven at 55-65 ℃ for drying for 3.5-4.5 hours, and the particles are dried at high temperature for a long time, so that impurities are easily generated.
A folic acid solid preparation and a preparation method thereof (application number: 201410499518.4) applied by Beijing Silian drug industry Co., Ltd adopts a dry granulation process, which comprises mixing lactose, starch and folic acid, dry-pressing and crushing by a dry press under the pressure of 0.5-1.5Mpa, and screening and collecting 24-65 mesh granules; magnesium stearate was added to the resulting granules, and the mixture was subjected to tableting. As is well known, when dry granulation is performed, a large amount of heat is generated when a compression roller runs for a long time to extrude materials, and the medicine is possibly unstable, so that the risk that the product cannot be avoided is brought in the process. In addition, the dry granulation process has high requirement on auxiliary materials, the auxiliary materials with good adhesiveness and fluidity need to be selected, and the auxiliary materials are expensive, so that huge cost and trouble are brought to pharmaceutical companies.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of a novel folic acid solid preparation. The invention adopts a wet granulation or one-step granulation process, folic acid is dispersed in a stabilizer solution and then granulated with an excipient, or folic acid and the excipient are mixed and then granulated by using the stabilizer solution as an adhesive, thereby skillfully solving the problems of poor stability of tablets, uneven medicine mixing, color spots on the tablet surface and the like. The solid preparation prepared by the invention can meet the requirement that related substances do not have obvious change in the 6-month placing process under the acceleration condition; also has excellent dissolution effect, and the dissolution rate can reach more than 90 percent within 15 minutes.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing folic acid solid preparation is characterized in that folic acid is used as an active ingredient and pharmaceutic adjuvants are prepared, wherein the pharmaceutic adjuvants comprise a stabilizer, an excipient and a lubricant; every 1000 tablets of the folic acid solid preparation are composed of the following components in parts by weight: 0.4-5g of folic acid, 5-15g of stabilizer, 70-90g of excipient and 0.1-2.0g of lubricant;
the stabilizing agent is selected from polyethylene glycol with the molecular weight range of 3350, 4000 or 6000;
the excipient is selected from two or more of microcrystalline cellulose, corn starch, pregelatinized starch, lactose, sucrose, dextrin, mannitol, xylitol and calcium hydrogen phosphate;
the lubricant is one or more of talcum powder, silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate and is prepared by the following method:
the method comprises the following steps: crushing folic acid and sieving with a 200-mesh sieve;
step two: granulating the crushed folic acid, excipient and stabilizer;
step three: drying the obtained granules at 40-70 deg.C;
step four: granulating the dried granules with a 20-30 mesh screen;
step five: adding a lubricant into the granules and mixing for 5-10 minutes;
step six: tabletting, and controlling the hardness of the tablets to be 2-6 kg; or directly encapsulating the granules.
The invention further discloses an application of the preparation method of the folic acid solid preparation in improving the stability of the folic acid solid preparation. The experimental results show that: the folic acid solid preparation prepared by the invention has good stability, even medicine mixing and no color spots on the surface. The solid preparation prepared by the invention can meet the requirement that related substances have no significant change in the 6-month placing process under the acceleration condition; also has excellent dissolution effect, and the dissolution rate can reach more than 90 percent within 15 minutes.
The invention is described in more detail below: a solid folic acid preparation is prepared from folic acid as active component and medicinal auxiliaries including stabilizer, excipient and lubricant.
Every 1000 tablets of the folic acid solid preparation are composed of the following components in parts by weight: 0.4-5g of folic acid, 5-15g of stabilizer, 70-90g of excipient and 0.1-2.0g of lubricant.
Wherein the stabilizer is selected from one of hydroxypropyl methylcellulose, povidone, copovidone, polyethylene glycol and hydroxypropyl cellulose. The preferred stabilizer is polyethylene glycol. Wherein the stabilizer polyethylene glycol has a molecular weight in the range of 1000 to 8000; the preferred molecular weight range of the stabilizer polyethylene glycol is one of 3350, 4000, or 6000.
The excipient is selected from two or more of microcrystalline cellulose, corn starch, pregelatinized starch, lactose, sucrose, dextrin, mannitol, xylitol, and calcium hydrogen phosphate. Wherein the two compositions are corn starch and lactose, pregelatinized starch and calcium hydrogen phosphate, pregelatinized starch and microcrystalline cellulose; the part ratio is 1: 3. the two or more compositions are corn starch, mannitol and lactose, pregelatinized starch, lactose and calcium hydrogen phosphate, pregelatinized starch, microcrystalline cellulose and calcium hydrogen phosphate; wherein the part ratio is 1: 3: 5.
preferred excipient combinations are dibasic calcium phosphate, microcrystalline cellulose and pregelatinized starch.
The lubricant is one or more of colloidal silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate. Wherein one or more of the compositions are silicon dioxide and magnesium stearate, colloidal silicon dioxide and magnesium stearate, silicon dioxide and stearic acid, silicon dioxide and sodium stearyl fumarate; wherein the part ratio is 2: 3. a preferred combination of lubricants is silicon dioxide and magnesium stearate.
The preparation method of the folic acid solid preparation is characterized by comprising the following preparation steps:
the method comprises the following steps: the folic acid is crushed and sieved, and the mesh is 100 to 200;
step two: granulating the crushed folic acid, excipient and stabilizer;
step three: drying the obtained granules at 40-70 deg.C;
step four: granulating the dried granules with a 20-30 mesh screen;
step five: adding a lubricant into the granules and mixing for 5-10 minutes;
step six: tabletting, and controlling the hardness of the tablets to be 2-6 kg; or directly encapsulating the granules.
Further, the preparation method of the folic acid solid preparation is characterized by comprising the following preparation steps:
the method comprises the following steps: crushing and sieving folic acid, and sieving with a 200-mesh sieve;
step two: mixing the crushed folic acid, calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch, and granulating by using a polyethylene glycol solution;
step three: transferring the prepared wet granules to a fluidized bed at 40-60 ℃ for drying for 10-30 minutes;
step four: granulating the dried granules with a 20-30 mesh screen;
step five: transferring the granules to a mixer, adding silicon dioxide and magnesium stearate, and mixing for 5-10 minutes;
step six: tabletting, and controlling the hardness of the tablets to be 2-6 kg; or directly encapsulating the granules.
Further, the solvent of the polyethylene glycol solution can be purified water, 95% ethanol, and a mixture of ethanol and water in any proportion.
The folic acid solid preparation obtained by the technical scheme can ideally achieve the aims and technical effects of the invention, and specifically, the folic acid solid preparation and the preparation method thereof can achieve the following effects:
(1) the obtained folic acid solid preparation has less related substances increase and good stability.
(2) Excellent elution effect.
(3) Stable technological process, good quality reproducibility and controllable quality.
It should be noted that, in order to make the contents and technical connotations of the present invention more clearly understood by those skilled in the art, the inventor of the present invention makes the following descriptions of the related terms and symbols, applied to the reagent consumables and the apparatus and equipment:
"day 0": refers to the time when sample preparation is complete;
"acceleration condition": the temperature is 40 ℃ plus or minus 2 ℃, and the relative humidity is 75% + orminus 5%.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available. In order to facilitate understanding of the present invention by those skilled in the art, the present invention provides the following embodiments to further explain the folic acid solid preparation and the preparation method thereof:
example 1
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing and sieving folic acid, and sieving with 200 mesh sieve;
2. mixing the crushed folic acid, calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch, and granulating by using a polyethylene glycol solution;
3. the wet granules obtained were transferred to a fluidized bed at 70 ℃ for drying for about 15 minutes;
4. granulating the dried granules by using a 24-mesh screen;
5. the granules were transferred to a blender and mixed for 5 minutes with the addition of silicon dioxide and magnesium stearate;
6. tabletting, and controlling the hardness of the tablets to be 3 kg.
Example 2
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing and sieving folic acid, and sieving with 200 mesh sieve;
2. dispersing the crushed folic acid in a polyethylene glycol aqueous solution, and mixing with calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch for granulation;
3. the wet granules obtained were transferred to a fluidized bed at 60 ℃ for drying for about 15 minutes;
4. granulating the dried granules by using a 30-mesh screen;
5. the granules were transferred to a blender and blended with silicon dioxide and magnesium stearate for 10 minutes;
6. tabletting, and controlling the hardness of the tablets to be 3 kg.
Example 3
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing and sieving folic acid, and sieving with 200 mesh sieve;
2. dispersing the crushed folic acid in a polyethylene glycol ethanol solution, and mixing with calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch for granulation;
3. the wet granules obtained were transferred to a fluidized bed at 50 ℃ for about 30 minutes to dry;
4. granulating the dried granules by using a 24-mesh screen;
5. the granules were transferred to a blender and mixed for 5 minutes with the addition of silicon dioxide and magnesium stearate;
6. tabletting, and controlling the hardness of the tablets to be 3 kg.
Example 4
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing and sieving folic acid, and sieving with 200 mesh sieve;
2. mixing the crushed folic acid, calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch, and granulating by using a polyethylene glycol solution;
3. the wet granules obtained were transferred to a fluidized bed at 40 ℃ for about 30 minutes to dry;
4. granulating the dried granules by using a 24-mesh screen;
5. the granules were transferred to a blender and mixed for 5 minutes with the addition of silicon dioxide and magnesium stearate;
6. tabletting, and controlling the hardness of the tablet to be 4 kg.
Example 5
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing folic acid and sieving with a 200-mesh sieve;
2. dispersing the crushed folic acid in a polyethylene glycol aqueous solution, and mixing with calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch for granulation;
3. the wet granules obtained were transferred to a fluidized bed at 60 ℃ for drying for about 15 minutes;
4. granulating the dried granules by using a 24-mesh screen;
5. transferring the granules to a mixer, adding silicon dioxide and stearic acid, and mixing for 5 minutes;
6. the granules are filled into capsules.
Comparative example 1
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. crushing folic acid and sieving with a 200-mesh sieve;
2. mixing the crushed folic acid and the pregelatinized starch by an equivalent progressive method, and then uniformly mixing the folic acid, the calcium hydrophosphate and the microcrystalline cellulose;
3. adding silicon dioxide and magnesium stearate and mixing for 5 minutes;
4. tabletting, and controlling the hardness of the tablets to be 3 kg.
Comparative example 2
Prescription (1000 tablets)
The preparation method comprises the following steps:
1. the folic acid, D90, was used at 210 μm;
2. dispersing the crushed folic acid in a polyethylene glycol 4000 aqueous solution, and mixing with calcium hydrophosphate, microcrystalline cellulose and pregelatinized starch for granulation;
3. the wet granules obtained were transferred to a fluidized bed at 60 ℃ for drying for about 20 minutes;
4. granulating the dried granules by using a 24-mesh screen;
5. the granules were transferred to a blender and mixed for 5 minutes with the addition of silicon dioxide and magnesium stearate;
6. tabletting, and controlling the hardness of the tablets to be 3 kg.
Test example 1
And (3) related substance inspection:
the intermediates of examples 1-5 and comparative example 1 are packaged according to the market, and are placed under the acceleration condition with the commercial preparation, taken out at 0, 3 and 6 months, related substances are detected, and the stability of the sample is examined; according to the related substance inspection method under the folic acid tablet item in the current Chinese pharmacopoeia, the related substances of the examples 1-5, the comparative example 1 and the commercial preparation are inspected, and the results are as follows:
the inspection results of related substances show that: after the samples of the examples 1 to 5 are subjected to the acceleration condition for 6 months, the contents of the maximum single impurity, the pteroic acid and the total impurity in related substances are obviously smaller than those of the commercial preparation and the sample of the comparative example 1, and the increase amplitude of each impurity is small; in addition, according to the regulation of related substances under the folic acid tablet item in the current Chinese pharmacopoeia: pteroic acid is not more than 0.6%, the maximum single impurity is not more than 1.0%, the total impurities (except pteroic acid) are not more than 3.0%, and the maximum single impurity in the commercial preparation and the related substances of the sample of comparative example 1 is out of limits after 3 months under accelerated conditions. The preparation method can obtain samples with good related substance level and high stability.
Test example 2
According to the content uniformity detection method in the existing Chinese pharmacopoeia, the content uniformity detection is carried out on the examples 1-5, the comparative example 1 and the commercially available preparation, and the results are as follows:
the data in the table show that the content uniformity of the folic acid tablets prepared according to the invention is good, and the result is far less than the requirement that A +2.2S is less than or equal to 15.0 specified in the current Chinese pharmacopoeia. And is superior to the folic acid tablet prepared by the powder direct compression process in the commercial preparation and the comparative example 1.
Test example 3
And (3) dissolution rate inspection:
according to the dissolution rate detection method under the item of folic acid tablets in the current Chinese pharmacopoeia, the detection is carried out, and the results are as follows:
according to the dissolution rate regulation of the folic acid tablets in the current Chinese pharmacopoeia, the dissolution rate is not less than 75 percent in 30 minutes. The dissolution rate of the invention in 30 minutes is higher than 90%, which is obviously higher than that of the comparative example 1, the comparative example 2 and the commercial preparations, and the invention has excellent dissolution effect.
The above description of the embodiments is only intended to facilitate the understanding of the method and the core idea of the present invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications are also within the scope of the present invention as defined in the appended claims.
Claims (2)
1. A method for preparing folic acid solid preparation is characterized in that folic acid is used as an active ingredient and pharmaceutic adjuvants are prepared, wherein the pharmaceutic adjuvants comprise a stabilizer, an excipient and a lubricant; every 1000 tablets of the folic acid solid preparation are composed of the following components in parts by weight: 0.4-5g of folic acid, 5-15g of stabilizer, 70-90g of excipient and 0.1-2.0g of lubricant;
the stabilizing agent is selected from polyethylene glycol with the molecular weight range of 3350, 4000 or 6000;
the excipient is selected from two or more of microcrystalline cellulose, corn starch, pregelatinized starch, lactose, sucrose, dextrin, mannitol, xylitol and calcium hydrogen phosphate;
the lubricant is one or more of talcum powder, silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate and is prepared by the following method:
the method comprises the following steps: crushing folic acid and sieving with a 200-mesh sieve;
step two: granulating the crushed folic acid, excipient and stabilizer;
step three: drying the obtained granules at 40-70 deg.C;
step four: granulating the dried granules with a 20-30 mesh screen;
step five: adding a lubricant into the granules and mixing for 5-10 minutes;
step six: tabletting, and controlling the hardness of the tablets to be 2-6 kg; or directly encapsulating the granules.
2. Use of a solid formulation of folic acid prepared by the method of claim 1 to improve the stability of a solid formulation of folic acid.
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| CN114767645A (en) * | 2022-04-27 | 2022-07-22 | 北京斯利安药业有限公司 | Folic acid tablet and preparation method thereof |
| CN114983954A (en) * | 2022-06-15 | 2022-09-02 | 广州新济药业科技有限公司 | Folic acid tablet and preparation method thereof |
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Application publication date: 20211231 |