CN101455671A - Mifepristone medicinal preparation and preparation method thereof - Google Patents
Mifepristone medicinal preparation and preparation method thereof Download PDFInfo
- Publication number
- CN101455671A CN101455671A CNA2009100604566A CN200910060456A CN101455671A CN 101455671 A CN101455671 A CN 101455671A CN A2009100604566 A CNA2009100604566 A CN A2009100604566A CN 200910060456 A CN200910060456 A CN 200910060456A CN 101455671 A CN101455671 A CN 101455671A
- Authority
- CN
- China
- Prior art keywords
- mifepristone
- preparation
- pharmaceutical preparation
- preparation according
- starch
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 title claims abstract description 85
- 229960003248 mifepristone Drugs 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 229920002472 Starch Polymers 0.000 claims abstract description 20
- 239000008107 starch Substances 0.000 claims abstract description 20
- 235000019698 starch Nutrition 0.000 claims abstract description 20
- 239000000843 powder Substances 0.000 claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 13
- 229920001353 Dextrin Polymers 0.000 claims abstract description 10
- 239000004375 Dextrin Substances 0.000 claims abstract description 10
- 235000019425 dextrin Nutrition 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229960003943 hypromellose Drugs 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group 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 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229920003091 Methocel™ Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 16
- 230000035935 pregnancy Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 241001465754 Metazoa Species 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 11
- 239000002775 capsule Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000004531 microgranule Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 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 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000003623 progesteronic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000011121 vaginal smear Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a mifepristone medicinal preparation and a preparation method thereof. The material is prepared by mixing the following raw materials in percentage by weight: 5-30% of mifepristone micro powder particles, 10-40% of microcrystalline cellulose, 2-10% of an adhesive, 20-40% of starch, 20-40% of dextrin, 0.5-2% of a lubricant and 0.5-1% of a glidant. The invention can improve the dissolution rate and bioavailability of the mifepristone preparation, obviously improve the effect of resisting early pregnancy of animals, and has simpler preparation method and low manufacturing cost.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof, specifically a kind of mifepristone pharmaceutical preparation and preparation method.
Background technology
Mifepristone, anti-progesterone drug, its chemical name name is called 11 β-[4-(N, N dimethylamine base) phenyl-17 beta-hydroxyl-17s-α-(1-propinyl)-female steroid-4,9-diene-3-ketone].1980 synthetic first by the Rousel-Ucalf company of France, now obtained clinical practice widely at home and abroad.Mifepristone 150mg compatibility prostaglandin uses the early pregnancy that can effectively stop in 49 days, and the effective percentage of its antiearly pregnancy reaches 92～94%.The emergency contraception effective percentage that mifepristone 10～25mg was used in 72 hours reaches more than 90%.
Mifepristone is water insoluble, but can be dissolved in the hydrochloric acid solution of 0.1m/L, and therefore the dissolution in water is very low, can affect the treatment after taking or the curative effect instability.It is a lot of with the report that improves its dissolution to make solid dispersion with Polyethylene Glycol and insoluble drug, but mostly is used to prepare drop pill because more difficult industrialization obtains.Do not see the prescription that increases the mifepristone stripping and the report of technology are arranged.Therefore, research and development are a kind of increases the technology of mifepristone preparation stripping and the preparation of prescription is very necessary.
Summary of the invention
Purpose of the present invention is exactly very low at the existing dissolution of mifepristone pharmaceutical preparation in water, can affect the treatment after taking or the unsettled defective of curative effect, a kind of mifepristone pharmaceutical preparation and preparation method are provided, it can improve the dissolution and the bioavailability of this pharmaceutical preparation, thereby improves the curative effect of medicine.
Technical scheme of the present invention is achieved in that it is mixed with by following raw materials by weight and forms:
Mifepristone micro powder granule 5～30%, microcrystalline Cellulose 10～40%, binding agent 2～10%,
Starch 20～40%, dextrin 20～40%, lubricant 0.5～2%, fluidizer 0.5～1%.
The present invention's technical scheme preferably is: described mifepristone micro powder granule is with mifepristone raw material heating for dissolving in polar solvent, drips the water cooling crystallization again, then drying and crushing to particle diameter below 5um.The best techniques scheme is to be cooled to 0 ℃ of left and right sides crystallization.Mifepristone solid isolated by filtration from solvent of separating out is come out, and obtains mifepristone at 40-80 ℃ of vacuum drying.Wherein said polar solvent is methanol, ethanol, isopropyl alcohol, normal propyl alcohol or n-butyl alcohol.
Binding agent of the present invention is polyvidone, Polyethylene Glycol, hyprolose, hydroxy methocel, hypromellose, methylcellulose, ethyl cellulose or starch slurry.Described lubricant is Pulvis Talci, stearic acid, magnesium stearate or calcium sulfate.Described fluidizer is micropowder silica gel or Pulvis Talci.The present invention can select lactose, sucrose, starch, dextrin as diluent.
Bibliographical information, mifepristone crystallize in non-polar solvens such as ethyl acetate and diisopropyl ether obtains the mifepristone solid.We find that after deliberation mifepristone is heating for dissolving in polar solvent, drip water then, the solution cooling crystallization, and its crystal formation of separating out is inconsistent with crystal formation in non-polar solven.Heating for dissolving in polar solvent drips water cooling then and separates out its dissolution of crystalline mifepristone and improve greatly.These polar solvents have the alcohols material of C1-C6, as methanol, ethanol, isopropyl alcohol, normal propyl alcohol, n-butyl alcohol etc.
Behind the mifepristone process micronization with this method preparation, the microgranule more than 80% is all below 5um, according to mifepristone tablet, capsular technology preparation, technology, the mifepristone solid preparation of preparation, its stripping is increased to more than 95%, and abortion ratio improves, and bioavailability is good.
Find through a large amount of tests, mifepristone tablet or capsule, its stripping is not high, though formulation and technology is adjusted, still can not be increased to very high level.The inventor finds that through a large amount of tests preferred scheme is as follows:
The mifepristone tablet recipe:
| Weight ratio (%) | |
| Mifepristone, |
10～30％ |
| |
10～20％ |
| Binding agent | 2～10％ |
| |
20～30％ |
| Dextrin | 20～30％ |
| Lubricant | 0.5～2％ |
| Fluidizer | 0.5～1％ |
Mifepristone capsule prescription:
| Weight ratio (%) | |
| Mifepristone, |
10～30％ |
| |
20～40％ |
| Binding agent | 2～10％ |
| |
20～30％ |
| |
20～30％ |
| Lubricant | 0.5～2％ |
| Fluidizer | 0.5～1％ |
The present invention can improve the dissolution and the bioavailability of mifepristone preparation, and it obviously increases the antiearly pregnancy effect of animal, and its preparation method is comparatively simple, low cost of manufacture.
Figure of description
Fig. 1 is the tablet stripping curve figure of mifepristone
Fig. 2 is the capsule stripping curve figure of mifepristone
The specific embodiment
Below in conjunction with embodiment the present invention is described further:
Embodiment 1
10g mifepristone raw material is heated in the alcoholic solution that is dissolved in 50ml about 70 ℃, drips water 50ml, cooling in this solution, after at room temperature keeping 3 hours, be cooled to then below 0 ℃, separate out crystal in the solution, filter, filtrate is washed with cold ethanol/water, and vacuum is dry below 50 ℃.Obtain mifepristone: 6g.HPLC purity: 99.54%, fusing point: 135-140 ℃.Mifepristone pulverized with micronization obtain mifepristone micronization particle size distribution result
| Numbering | Particle diameter um | Accumulation % | Interval % | Numbering | Particle diameter um | Accumulation % | Interval % |
| 1 | 0.39 | 0 | 0 | 11 | 2.15 | 44.53 | 13.41 |
| 2 | 0.46 | 0 | 0 | 12 | 2.55 | 59.84 | 1631 |
| 3 | 0.55 | 0.50 | 0.50 | 13 | 3.02 | 74.05 | 14.21 |
| 4 | 0.65 | 1.58 | 1.08 | 14 | 3.58 | 85.65 | 11.60 |
| 5 | 0.77 | 3.05 | 1.47 | 15 | 4.24 | 93.79 | 8.14 |
| 6 | 0.92 | 5.53 | 2.48 | 16 | 5.03 | 98.20 | 4.41 |
| 7 | 1.09 | 9.53 | 4.00 | 17 | 5.97 | 99.78 | 1.58 |
| 8 | 1.29 | 14.89 | 5.36 | 18 | 7.07 | 100.00 | 0.22 |
| 9 | 1.53 | 21.38 | 6.49 | 19 | 8.39 | 100.00 | 0.00 |
| 10 | 1.81 | 31.12 | 9.74 | 20 | 9.95 | 100.00 | 0.00 |
Embodiment 2
10g mifepristone raw material is heated in the butanol solution that is dissolved in 50ml about 70 ℃, drips water 50ml, cooling in this solution, after at room temperature keeping 3 hours, be cooled to then below 0 ℃, separate out crystal in the solution, filter, filtrate is used cold water washing, and vacuum is dry below 50 ℃.Obtain mifepristone: 6g.HPLC purity: 99.60%, fusing point: 135-140 ℃.Mifepristone pulverized with micronization obtain the mifepristone granule.
Embodiment 3
10g mifepristone raw material is heated in the aqueous isopropanol that is dissolved in 50ml about 70 ℃, drips water 50ml, cooling in this solution, after at room temperature keeping 3 hours, be cooled to then below 0 ℃, separate out crystal in the solution, filter, filtrate is used cold water washing, and vacuum is dry below 50 ℃.Obtain mifepristone: 6g.HPLC purity: 99.52%, fusing point: 135-140 ℃.Mifepristone pulverized with micronization obtain the mifepristone granule.
Embodiment 4
Pharmaceutical formulation (is example with 1000 slice, thin pieces)
Mifepristone 25g (95% is above below 5 microns)
Lactose 20g
Starch 20g
Microcrystalline Cellulose 18g
Dextrin 14g
2% hypromellose 26.7g
Magnesium stearate 1g
Micronized mifepristone, starch, lactose, microcrystalline Cellulose, dextrin are mixed, add 2% hypromellose and granulate, sieve behind the wet grain drying, add magnesium stearate, tabletting is made preparation.
Embodiment 5
Pharmaceutical formulation (is example with 1000 slice, thin pieces)
Mifepristone 25g (95% is above below 5 microns)
Starch 20g
Microcrystalline Cellulose 18g
Dextrin 14g
Polyethylene Glycol 26.7g
Magnesium stearate 1g
Micronized mifepristone, starch, microcrystalline Cellulose, dextrin are mixed, add Polyethylene Glycol and granulate, sieve behind the wet grain drying, add magnesium stearate, tabletting is made preparation.
Embodiment 6
Pharmaceutical formulation (is example with 1000 capsules)
Mifepristone 12.5g (95% above microgranule is below 5 microns)
Starch 50g
Microcrystalline Cellulose 45g
Micropowder silica gel 1.5g
8% starch slurry 70ml (dried starch 5.6g)
With micronized mifepristone, starch, microcrystalline Cellulose, add 8% starch slurry and granulate, sieve behind the wet grain drying, add micropowder silica gel, fill is in No. 4 hard capsules.
Embodiment 7
Pharmaceutical formulation (is example with 1000 capsules)
Mifepristone 12.5g (95% above microgranule is below 5 microns)
Starch 50g
Microcrystalline Cellulose 45g
Micropowder silica gel 1.5g
Polyvidone 5.6g
Micronized mifepristone, starch, microcrystalline Cellulose are mixed, add polyvidone and granulate, sieve behind the wet grain drying, add micropowder silica gel, fill is in No. 4 hard capsules.
Pharmacological testing:
Mifepristone is carried out micronization, and the particle diameter that makes 80% microgranule is below 5 microns.Mifepristone powder, other pharmaceutic adjuvants are mixed, add the hypromellose binding agent and granulate, dry back adds other compositions and mixes the back tabletting promptly.Its dissolution sees Table 1, and its stripping curve is seen Fig. 1.
The tablet of the mifepristone of table 1 different-grain diameter is to the influence of dissolution
| 90% mifepristone |
30 minutes dissolution rate |
| Diameter of particle more than 90% is more than 50um | 70% |
| Below the diameter of particle 50um more than 90%, more than 10um. | 85% |
| Below the diameter of particle 5um more than 90% | 99% |
By table 1 as seen, when mifepristone diameter of particle 5um was following, 30 minutes stripping quantity surpassed more than 95%.
Mifepristone is carried out micronization, and the particle diameter that makes 90% microgranule is below 5 microns.Mifepristone powder, other adjuvants are mixed, add the starch slurry binding agent and granulate, dry back adds other compositions and mixes back fills in No. 4 capsules, promptly.Its dissolution sees Table 2.Its stripping curve is seen Fig. 2.
The capsule of the mifepristone of table 2 different-grain diameter is to the influence of dissolution
| The particle size range of |
30 minutes stripping |
| Rate | |
| Diameter of particle more than 80% is more than 100um | 70% |
| Below the diameter of particle 50um more than 90%, more than 10um. | 85% |
| Below the diameter of particle 5um more than 80% | 98% |
By table 2 as seen, when mifepristone diameter of particle 5um was following, 30 minutes stripping quantity surpassed more than 95%.
Long-term stable experiment and accelerated test investigation after two aluminum packings the results are shown in Table 3,4 for the tablet among the embodiment 4.
40 ℃ of investigation results that keep sample of table 3 mifepristone sheet
| Test item | Outward appearance | Content (%) | Catabolite | Dissolution (%) |
| January | Yellowish color chips | 102.1 | Do not detect | 98.5％ |
| February | Yellowish color chips | 101.5 | Do not detect | 99.2 |
| March | Yellowish color chips | 100.8 | Do not detect | 98.3 |
| June | Yellowish color chips | 101.7 | Do not detect | 98.9 |
The table 4 mifepristone sheet investigation result that keeps sample for a long time
| Test item | Outward appearance | Content (%) | Catabolite | Dissolution (%) |
| March | Yellowish color chips | 102.3 | Do not detect | 99.7 |
| June | Yellowish color chips | 101.9 | Do not detect | 99.5 |
| JIUYUE | Yellowish color chips | 102.1 | Do not detect | 98.9 |
| December | Yellowish color chips | 100.0 | Do not detect | 98.0 |
| 18 months | Yellowish color chips | 100.3 | Do not detect | 98.6 |
| 24 months | Yellowish color chips | 100.5 | Do not detect | 99.3 |
| 36 months | Yellowish color chips | 101.8 | Do not detect | 98.7 |
| 48 months | Yellowish color chips | 100.1 | Do not detect | 99.8 |
Investigate and the results are shown in Table 5,6. for the long-term stable experiment and the accelerated test of the capsule among the embodiment 6 after aluminum-plastic packaged
40 ℃ of investigation results that keep sample of table 5 mifepristone capsule
| Test item | Outward appearance | Content (%) | Catabolite | Dissolution (%) |
| January | Pale yellow powder | 100.9 | Do not detect | 99.3％ |
| February | Pale yellow powder | 100.8 | Do not detect | 99.0 |
| March | Pale yellow powder | 99.8 | Do not detect | 99.4 |
| June | Pale yellow powder | 100.7 | Do not detect | 97.9 |
The table 6 mifepristone capsule investigation result that keeps sample for a long time
| Test item | Outward appearance | Content (%) | Catabolite | Dissolution (%) |
| March | Pale yellow powder | 101.1 | Do not detect | 98.4 |
| June | Pale yellow powder | 100.4 | Do not detect | 96.4 |
| JIUYUE | Pale yellow powder | 102.8 | Do not detect | 99.3 |
| December | Pale yellow powder | 100.2 | Do not detect | 99.1 |
| 18 months | Pale yellow powder | 100.9 | Do not detect | 98.2 |
| 24 months | Pale yellow powder | 102.3 | Do not detect | 97.9 |
| 36 months | Pale yellow powder | 100.5 | Do not detect | 99.9 |
| 48 months | Pale yellow powder | 100.6 | Do not detect | 98.3 |
As seen from the above table, tablet of the present invention is stable, therefore can produce.
Test 1: mifepristone preparation of the present invention is to the antiearly pregnancy effect of rat
Getting the sexual maturity that body weight is 180～250g, the rat of unpregnancy and the male rat that body weight is 250～320g mates, make vaginal smear every morning, find sperm work gestation the 1st day, carry out gastric infusion at the 7th～10 day dosage and reach 3 days that the result is as shown in table 1 below according to following table 1:
The conventional mifepristone of producing (not micronization) on table 1 market, the mifepristone preparation produced according to patented method are to the antiearly pregnancy effect of rat
| Group | Dosage (mg/kg) | The animal pregnancy number | Total number of animals | Pregnancy rate % | Litter size |
| Matched group | Not |
10 | 10 | 100 | 10.3+1.5 |
| Conventional mifepristone on the market (not micronization) | 2.8 | 4 | 10 | 40 | 6.0±4.4 |
| Mifepristone tablet according to patented method production | 2.8 | 0 | 10 | 0 | 0 |
| Used adjuvant in the preparation | 2.8 | 10 | 10 | 100 | 9.8±2.8 |
From above-mentioned result of the test as seen, also not carrying out micronization with the mifepristone for preparing with the non-polar solven crystallize compares, mifepristone preparation of the present invention obviously increases the antiearly pregnancy effect of animal, and uses adjuvant used in the preparation not have the antiearly pregnancy effect separately.Mifepristone preparation of the present invention has the high advantage of bioavailability, and its preparation method is comparatively simple, convenient.
Claims (6)
1, a kind of mifepristone pharmaceutical preparation, it is mixed with by following raw materials by weight and forms:
Mifepristone micro powder granule 5～30%, microcrystalline Cellulose 10～40%, binding agent 2～10%, starch 20～40%, dextrin 20～40%, lubricant 0.5～2%, fluidizer 0.5～1%.
2, a kind of mifepristone pharmaceutical preparation according to claim 1, wherein said mifepristone micro powder granule is with mifepristone raw material heating for dissolving in polar solvent, drips the water cooling crystallization again, then drying and crushing to particle diameter below 5um.
3, a kind of mifepristone pharmaceutical preparation according to claim 2, wherein said polar solvent is methanol, ethanol, isopropyl alcohol, normal propyl alcohol or n-butyl alcohol.
4, a kind of mifepristone pharmaceutical preparation according to claim 1, wherein said binding agent is polyvidone, Polyethylene Glycol, hyprolose, hydroxy methocel, hypromellose, methylcellulose, ethyl cellulose or starch slurry.
5, a kind of mifepristone pharmaceutical preparation according to claim 1, wherein said lubricant is Pulvis Talci, stearic acid, magnesium stearate or calcium sulfate.
6, a kind of mifepristone pharmaceutical preparation according to claim 1, wherein said fluidizer is micropowder silica gel or Pulvis Talci.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100604566A CN101455671A (en) | 2009-01-08 | 2009-01-08 | Mifepristone medicinal preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100604566A CN101455671A (en) | 2009-01-08 | 2009-01-08 | Mifepristone medicinal preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101455671A true CN101455671A (en) | 2009-06-17 |
Family
ID=40766970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100604566A Pending CN101455671A (en) | 2009-01-08 | 2009-01-08 | Mifepristone medicinal preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101455671A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102107007A (en) * | 2011-01-28 | 2011-06-29 | 广州朗圣药业有限公司 | Sterides anti-progestogen composition and preparation method thereof |
| WO2012083801A1 (en) * | 2010-12-20 | 2012-06-28 | 广州朗圣药业有限公司 | Streoidal anti-progesterone composition, preparation method therefor, and use thereof |
| CN102614192A (en) * | 2011-01-31 | 2012-08-01 | 北京紫竹药业有限公司 | Medical composition for emergency contraception |
| CN102106805B (en) * | 2009-12-29 | 2013-06-12 | 上海中西制药有限公司 | Cymipristone solid preparation and preparation methods thereof |
| ITFI20120127A1 (en) * | 2012-06-21 | 2013-12-22 | Valpharma Internat Spa | FORMULATIONS FOR THE PREPARATION OF TABLETS FOR IMMEDIATE RELEASE ORAL TABLETS CONTAINING LOW-DOSE MIFEPRISTONS, SO OBTAINED THEREOF TABLETS AND THEIR PREPARATION PROCESS. |
| ITFI20120128A1 (en) * | 2012-06-21 | 2013-12-22 | Valpharma Internat Spa | FORMULATIONS FOR THE PREPARATION OF TABLETS FOR IMMEDIATE RELEASE ORAL TABLETS CONTAINING LOW-DOSE MIFEPRISTONS FOR THE TREATMENT OF ENDOMETRIOSIS, SO OBTAINED THESE TABLETS AND THEIR PREPARATION PROCESS. |
| CN103932998A (en) * | 2014-02-27 | 2014-07-23 | 范开华 | Orally disintegrating tablet of dry mifepristone emulsion, and preparation method thereof |
| US20230085008A1 (en) * | 2021-09-06 | 2023-03-16 | Slayback Pharma Llc | Pharmaceutical compositions of mifepristone |
-
2009
- 2009-01-08 CN CNA2009100604566A patent/CN101455671A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106805B (en) * | 2009-12-29 | 2013-06-12 | 上海中西制药有限公司 | Cymipristone solid preparation and preparation methods thereof |
| WO2012083801A1 (en) * | 2010-12-20 | 2012-06-28 | 广州朗圣药业有限公司 | Streoidal anti-progesterone composition, preparation method therefor, and use thereof |
| CN102107007A (en) * | 2011-01-28 | 2011-06-29 | 广州朗圣药业有限公司 | Sterides anti-progestogen composition and preparation method thereof |
| CN102107007B (en) * | 2011-01-28 | 2012-11-07 | 广州朗圣药业有限公司 | Sterides anti-progestogen composition and preparation method thereof |
| CN102614192A (en) * | 2011-01-31 | 2012-08-01 | 北京紫竹药业有限公司 | Medical composition for emergency contraception |
| ITFI20120128A1 (en) * | 2012-06-21 | 2013-12-22 | Valpharma Internat Spa | FORMULATIONS FOR THE PREPARATION OF TABLETS FOR IMMEDIATE RELEASE ORAL TABLETS CONTAINING LOW-DOSE MIFEPRISTONS FOR THE TREATMENT OF ENDOMETRIOSIS, SO OBTAINED THESE TABLETS AND THEIR PREPARATION PROCESS. |
| ITFI20120127A1 (en) * | 2012-06-21 | 2013-12-22 | Valpharma Internat Spa | FORMULATIONS FOR THE PREPARATION OF TABLETS FOR IMMEDIATE RELEASE ORAL TABLETS CONTAINING LOW-DOSE MIFEPRISTONS, SO OBTAINED THEREOF TABLETS AND THEIR PREPARATION PROCESS. |
| WO2013190098A1 (en) * | 2012-06-21 | 2013-12-27 | Valpharma International S.P.A. | Formulations for the preparation of immediate-release tablets for oral use containing low-dose mifepristone for the treatment of endometriosis, tablets thus obtained and their preparation process |
| WO2013190097A1 (en) * | 2012-06-21 | 2013-12-27 | Valpharma International S.P.A. | Formulations for the preparation of immediate-release tablets for oral administration containing low-dose mifepristone, tablets thus obtained and their preparation process |
| CN104540496A (en) * | 2012-06-21 | 2015-04-22 | 瓦尔法玛国际公司 | Formulations for the preparation of immediate-release tablets for oral administration containing low-dose mifepristone, tablets thus obtained and their preparation process |
| CN103932998A (en) * | 2014-02-27 | 2014-07-23 | 范开华 | Orally disintegrating tablet of dry mifepristone emulsion, and preparation method thereof |
| CN103932998B (en) * | 2014-02-27 | 2016-03-30 | 范开华 | A kind of mifepristone does newborn oral cavity disintegration tablet and preparation method thereof |
| US20230085008A1 (en) * | 2021-09-06 | 2023-03-16 | Slayback Pharma Llc | Pharmaceutical compositions of mifepristone |
| US11878025B2 (en) * | 2021-09-06 | 2024-01-23 | Slayback Pharma Llc | Pharmaceutical compositions of mifepristone |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101455671A (en) | Mifepristone medicinal preparation and preparation method thereof | |
| US20140072526A1 (en) | Method for the production of adsorbates of a rasagiline salt having a water-soluble adjuvant | |
| CN105646584B (en) | Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and its preparation method and application | |
| CN105837464A (en) | Sacubitril sodium crystal forms, preparation method and application thereof | |
| CN102429880B (en) | Dasatinib tablet | |
| CN104940148B (en) | A kind of mosapride citrate particle and preparation method thereof | |
| CN103193798A (en) | Cefixime compound and pharmaceutical composition thereof | |
| CN107951841A (en) | A kind of Nimodipine solid dispersoid and its method for preparing tablet thereof | |
| CN103204859B (en) | A kind of Nalmefene hydrochloride compound and preparation method thereof | |
| JP5809367B2 (en) | Crystalline polymorph α of levonorgestrel and method for producing the same | |
| CN103006595B (en) | The method for preparing ulipristal acetate | |
| CN106983752B (en) | Preparation method of valsartan and hydrochlorothiazide capsules | |
| WO2014175304A1 (en) | β CRYSTALLINE POLYMORPH OF LEVONORGESTREL, AND MANUFACTURING METHOD FOR SAME | |
| CN105435144A (en) | Raw ginger micro-pill and preparation method thereof | |
| CN105560603A (en) | Novel tea polyphenol spherical particles | |
| KR101418937B1 (en) | Preparations for oral administration with enhanced bioavailability of megestrol acetate and Method for enhancing bioavailability of oral megestrol acetate preparations | |
| KR20190001714A (en) | Method of manufacturing Choline Alfoscerate solid particles, Choline Alfoscerate solid formulations using thereof and Choline Alfoscerate particles | |
| CN113134007B (en) | Abiraterone acetate oral preparation and preparation method thereof | |
| CN102911226A (en) | Erythromycin derivative and preparation method and applications thereof | |
| CN105237607B (en) | Uliprista acetate crystalline substance K-type substance and preparation method and its composition and purposes | |
| WO2017168476A1 (en) | Anti-tritrichomonas agent | |
| CN105520966A (en) | Hericium erinaceus micro-pills and preparation method thereof | |
| JP6433910B2 (en) | Novel crystal mixture of levonorgestrel and process for producing the same | |
| CN104666355A (en) | Propolis pellets and preparation method thereof | |
| CN102311430A (en) | Novel crystalline state of iloperidone and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20090617 |