CN1255107C - Composition of mifepristone semi-solid skeleton preparation - Google Patents

Composition of mifepristone semi-solid skeleton preparation Download PDF

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Publication number
CN1255107C
CN1255107C CNB021368376A CN02136837A CN1255107C CN 1255107 C CN1255107 C CN 1255107C CN B021368376 A CNB021368376 A CN B021368376A CN 02136837 A CN02136837 A CN 02136837A CN 1255107 C CN1255107 C CN 1255107C
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mifepristone
present
polyoxyethylene
semi
capsule
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CN1408356A (en
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顾林金
吴良信
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Shenzhen Fu Fu Industrial Co Ltd
Shanghai Institute of Pharmaceutical Industry
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Shenzhen Fu Fu Industrial Co Ltd
Shanghai Institute of Pharmaceutical Industry
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Priority to PCT/CN2003/000741 priority patent/WO2004022067A1/en
Priority to AU2003261600A priority patent/AU2003261600A1/en
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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses the composition of mifepristone semi-solid skeleton preparation. The present invention comprises the components and the content of 0.5 to 5 wt% of mifepristone, 1 to 50 wt% of surface active agents of which the HLB is more than 12, and 45 to 98.5 wt% of semi-solid skeleton carriers. The present invention has good dissolution performance and high early-pregnancy resistance. The rat Ed50 of the present invention is 17 times more than market troches. The bioavailability of dogs is 5 times more than market troches. The present invention adopts multi-centric random double-blind clinical research (240 pairs). One third dosage of the present invention 50 mg achieves the same clinical effect as market troches 150 mg. The mifepristone capsules of the present invention have the advantages of low dosage, little adverse reaction and high bioavailability.

Description

The compositions of mifepristone semi-solid skeleton preparation
Technical field
The present invention relates to a kind of mifepristone preparation.
Background technology
Mifepristone, its English name are mifepristone, and its chemical name is 11 β-[4-(N, N dimethylamine base) phenyl]-17 beta-hydroxyl-17 alphas-(1 propinyl) female steroid-4,9-diene-3-ketone 1,3, and its structural formula is as follows:
Molecular formula is C 29H 35NO 2, molecular weight is 429.61.
Chinese patent 86102502 discloses mifepristone and preparation method thereof.Mifepristone is a kind of acceptor levels gestation antagonist, has termination of early pregnancy, anti-implantation, induces the effect of menstruation and cervix maturation-stimulating.Be widely used in the antiearly pregnancy emergency contraception clinically, and had good effect.New indication treatment hysteromyoma, endometriosis, breast carcinoma, depression etc. are also among developmental research.
As novel endometrium progesterone receptor antagonists, mifepristone has effective advantage easy to use, safe.Because when poorly water soluble drugs was absorbed by digestive tract in the body, its absorbance and its dissolubility were directly proportional usually.Mifepristone is a water-insoluble drug, and therefore oral back, for reaching the clinical efficacy of expection, is had to strengthen clinical dosage, and produced untoward reaction and expensive problem gastrointestinal absorbance lower (absolute biological sharp degree is 30～50%).
In order to overcome the above problems, many Patent publish technology separately, to overcome the shortcoming of oral absorption difference, improve biological sharp degree in the hope of reaching, reduce dosage, reduce the not purpose of excellent reaction.Form compound recipe to reduce principal agent dosage as: Chinese patent CN1111512A medical composition for prevention of early pregnancy with mifepristone and anorethindrane dipropionate and the pharmaceutically acceptable carrier of surplus, reduce unexcellent reaction.Chinese patent CN1218665A high efficiency mifepristone preparation, Chinese patent CN1311000A mifepristone capsule and preparation method thereof is a kind of soft gelatin capsule that contains mifepristone, includes mifepristone solution and the gelatin that adjuvants such as mifepristone and propylene glycol, ethanol, tween 20, Polyethylene Glycol-400 make and makes as outer covering material.Above-mentioned patent is from present performance, except that CN1218665A, certain curative effect is all arranged, but the former antiearly pregnancy clinical effectiveness also not ideal (about effective percentage 90%), the latter's antiearly pregnancy clinical dosage is reduced to the 75mg/ example from the 150mg/ example, has also only reduced a half-value dose.
In sum, also not having very good mifepristone preparation at present, therefore research and develop a kind of new mifepristone preparation, is the very urgent task of field of medicaments.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of mifepristone semi-solid skeleton preparation (Semi Solid Mairix), promptly in medicinal liquid, add material with wax shape fusing point sample, can hot melt when high temperature, it during room temperature solid, compare with traditional powder particle, it can avoid drug powder to fly upward (being particularly useful for hormone and anticarcinogen); Loadings is even, and principal agent dosage is accurate; Medicine or medicinal liquid are scattered in the excipient isolated with air and dampness, thereby more stable; Suitably adjust prescription, can obtain desired high biological sharp degree, in the hope of making pharmacological active substance mifepristone absorption in vivo better, the curative effect that obtains under lower dosage also reduces untoward reaction.
Preparation of the present invention comprises:
Mifepristone 0.5～5% (weight)
The surfactant 1～50% (weight) of HLB (hydrophile-lipophile balance value) more than 12
The carrier 45～98.5% (weight) of semi-solid backbone
The surfactant that meets above-mentioned condition comprises the polyoxyethylene castor oil double glyceride, polyoxyethylene (6) sorbitan mono-laurate sorbitan fatty acid esters (span) such as (span 20s), polyoxyethylene mono laurate Pyrusussuriensis ester, polyoxyethylene fatty acid Pyrusussuriensis esters (tween) such as polyoxyethylene list oleic acid Pyrusussuriensis ester, the polyoxyethylene alkyl ether of Brij30 etc., the cithrol of polyoxyethylene (10) monolaurate etc., polyoxyethylene castor oil, certain herbaceous plants with big flowers acid glyceryl laurate ester, the mixed fatty glycerides such as caproic acid glyceryl laurate ester and the mixture of two or more compositions in them.From water dispersible and secure context, preferably certain herbaceous plants with big flowers acid glyceryl laurate ester and polyoxyethylene mono laurate Pyrusussuriensis ester.
The carrier of used semi-solid backbone comprises one or more in Polyethylene Glycol, polyoxyethylene (40) stearate, poloxamer, polyoxyethylene sorbitan monostearate, 12～18 carbon fatty acid glyceride or the propylene glycol stearate among the present invention.Consider from water dispersible and technology, preferably polyoxyethylene sorbitan monostearate or poloxamer.
The main effect of said surfactant is the hydrophilic that increases mifepristone, promotes its absorption in vivo, and its hydrophile-lipophile balance value HLB value is big more, and its hydrophilic is also big more, and effect is also just stronger.
So surfactant can increase the dissolubility of insoluble drug in water, be commonly considered as because surfactant forms (Micelles) result of micelle (micelle) in water.Micelle is inwardly to form a minimum oil droplet (nonpolar center) by the lipophilic group of surfactant, hydrophilic group then outside (hydrophilic group of nonionic then from oil droplets as wavy to around stretch into aqueous phase) form spheroid.
Think that now micelle can insert solubilizate such as mifepristone in the oil droplet in the micelle with the nonpolar part of its molecule with polar molecule slightly, its polarity part then stretches between the hydrophilic group of the surfactant in the water and produces solubilization.
Surfactant has the effect of lipin dissolving when low concentration, can dissolve the phospholipid of gastrointestinal mucosal and change epithelial permeability, reduces the barrier action of intestinal mucosa lipoid.So many medicines that originally were difficult to absorb, add surfactant and make to absorb and increase by passive diffusion.Therefore the agent of HLB value higher surface activity can increase the dissolubility of mifepristone in water, can reduce the barrier action of intestinal mucosa lipoid again and increases its absorption in vivo.
Said semi-solid backbone carrier with substrate with certain HLB value for well, it has water solublity on the one hand, can be as the semisolid dispersion of poorly water soluble drugs, and certain liposoluble performance is arranged again, with can also form low-melting fused matter after mifepristone mixes, increase the medicine absorption in vivo.
Preparation of the present invention is preparation like this:
Each composition is quantitatively mixed according to the above ratio, stir, heating to make that preparation is easier to be carried out, with capsule liquid-filling machine (modular system is arranged) can be made into capsule, also available other equipment are made drop pill, powder etc.
Stability to the mifepristone semi-solid skeleton preparation that makes of the present invention is investigated:
This product is removed the directly naked illumination 3000LX, 40 ℃ of placing of outer package, and 25 ℃ of RH92.5% conditions are following 10 days in the air at room temperature, with the primary sample contrast, carry out character, catabolite inspection, dissolution, assay etc., and this product is basicly stable.This product was quickened 3 months under 40 ℃, RH75% condition and room storage 24 months and regularly investigate index observing by the quality standard of working out and measure under listing packing, and this product is basicly stable.
Each constituent of this product is contrast with the tablet, measures dissolution with the distillation water as medium, to show the superiority of each component:
Mifepristone is made into the semi-solid backbone type prescription A of 1% different component, B, C, D is as trial target, with former tablet is tester, do slightly to carry out the dissolution test after the change according to second method in 2000 editions Chinese Pharmacopoeia appendix XC dissolution methods: measure the distilled water 500ml that handles through the degassing, inject in each process container, heat and make water temperature remain on 37 ℃ ± 0.5 ℃, precision takes by weighing for test agent 2 grams, add respectively in 6 process containers, start rotation (100 rev/mins) immediately, and pick up counting, during to 30 minutes, in the sampling of regulation point, and filter through double-deck 0.8 μ m microporous filter membrane immediately, get subsequent filtrate to measure by the mifepristone content assaying method, calculate the stripping percentage rate, the results are shown in following table:
The stripping percentage rate of tablet and each component (%, 30 minutes)
Prescription Tablet A B C D
1 0 41.90 46.65 62.20 87.47
2 0 23.76 41.68 71.27 87.47
3 0 43.20 46.00 64.70 77.75
4 0 35.64 47.52 60.26 74.51
5 0 21.60 43.20 51.84 87.47
6 0 23.76 49.68 58.32 74.51
Mean value S 0 31.64±9.8 45.79±2.92 61.45±6.5 81.53±6.61
As can be seen from the table, tablet and component A, B, C, D stripping percentage rate in the time of 30 minutes is respectively 0,31.64%, 45.79%, 61.45% and 81.53%.Tablet not stripping substantially in distilled water (dissolution medium in the tablet quality standard is the 0.1mol/L hydrochloric acid solution) is described.Component D is best, and the stripping percentage rate is 81.53%.
The animal pharmacodynamics test:
Pregnant rat was irritated stomach in pregnant d 7-9 days and is given adjuvant and mifepristone capsule content, every day 1 time, totally 3 times.Gestation d observed embryo's situation in 14 days, saw the following form:
The mifepristone capsule content merges the antiearly pregnancy effect of misoprostol to rat
Group The normal pregnancy matched group The adjuvant group Various dose group μ g/kg
12.5 25 50 100 200
The laboratory animal number 17 10 8 10 10 10 9
The animal pregnancy number 15 10 7 7 5 2 1
Gestation control rate (%) 11.8 0 12.5 30 50 80 88.89
The Abott formula is corrected back pregnant control rate (%) 7.93 20.63 43.31 77.32 87.40
ED50 62.54±2 14.25μg/kg
95% fiducial limit, 276.44～801.72 μ g/kg
Commercially available mifepristone tablet merges the antiearly pregnancy effect of misoprostol to rat
Group The normal pregnancy matched group The adjuvant group Various dose group μ g/kg
62.5 125 250 500 1000
The laboratory animal number 17 10 8 10 10 9 9
The animal pregnancy number 15 10 8 7 6 4 3
Gestation control rate (%) 11.8 0 0 30 40 55.56 66367
The Abott formula is corrected back pregnant control rate (%) 0 20.63 31.90 49.61 62.21
ED50 580.02±214.25μg/kg
95% fiducial limit, 276.44～801.72 μ g/kg
By table as seen, mifepristone capsule content merging misoprostol is 62.54 ± 214.25 μ g/kg to the ED50 of the antiearly pregnancy effect of rat, 95% credible 276.44～801.72 μ g/kg that are limited to, the ED50 of commercially available mifepristone tablet is 580.02 ± 214.25 μ g/kg, (95% credible 276.44～801.72 μ g/kg that are limited to), show that the mifepristone capsule content has stronger antiearly pregnancy effect to rat than tablet, is about 9 times of tablet.
Pregnant rat is irritated stomach in pregnant d 6-7 and award adjuvant, mifepristone capsule 's content of the present invention and commercially available mifepristone tablet the morning, and every day 1 time, totally 2 pregnant d 14 observe embryo's situations.See Table A and table B.
Table A mifepristone capsule 's content of the present invention is to the antiearly pregnancy effect of rat
Dosage μ g/kg The number of animals of becoming pregnant n Become pregnant and suppress number n Suppression ratio % becomes pregnant Suppression ratio % becomes pregnant after the Abott formula is corrected
500 11 10 90.9 89.47
250 11 8 72.7 68.42
125 11 7 63.6 57.89
62.5 11 4 36.4 26.32
31.25 11 2 18.2 5.26
The adjuvant group 22 3 13.64
ED 50=126.6 μ g/kg, 95% fiducial limit (76.4-209.7 μ g/kg)
Machine calculates with the Bliss method as calculated: the mifepristone capsule 's content is to the ED of rat anti early pregnancy effect 50Be 126.6 μ g/kg, the 95% credible 76.4-209.7 μ g/kg that is limited to.
The commercially available mifepristone tablet of table B is to the antiearly pregnancy effect of rat
Dosage mg/kg The number of animals of becoming pregnant n Become pregnant and suppress number n Suppression ratio % becomes pregnant Suppression ratio % becomes pregnant after the Abott formula is corrected
8 10 10 100 100
4 10 8 80 76.84
2 10 5 50 42.10
1 10 3 30 18.95
0.5 10 1 10 0
The adjuvant group 22 3 13.64
ED 50=2162.9 μ g/kg, 95% fiducial limit (1428.9-3274 μ g/kg)
Machine calculates with the Bliss method as calculated: the mifepristone tablet is to the ED of rat anti early pregnancy effect 50Be 2163ug/kg, the 95% credible 1429-3274 μ g/kg that is limited to.
By Table A, B as seen, mifepristone capsule 's content of the present invention and marketed tablet are to the ED of rat anti early pregnancy 50Be respectively 126.6 μ g/kg and 2163 μ g/kg, mifepristone capsule 's content of the present invention is strong than tablet to the antiearly pregnancy effect of rat, is about 17 times of tablet.
By on can find out that semi-solid backbone type preparation of the present invention is to rat anti early pregnancy effect ED 50Be 17 times of marketed tablet, than mifepristone capsule to rat anti early pregnancy effect ED 509 times of being marketed tablet are much better than.
Mifepristone capsule animal relative bioavailability of the present invention experimental study:
With 6 of domesticated dogs is subjects, adopt consubstantiality cross matching method, the single intersection is irritated stomach on an empty stomach and is given mifepristone capsule of the present invention respectively, contain mifepristone 150mg, or be control formulation, 6 with the mifepristone tablet that Xianju, Zhejiang Pharmacy stock Co., Ltd produces, contain mifepristone 150mg, adopt high effective liquid chromatography for measuring different time blood plasma Chinese medicine concentration,, tried to achieve main pharmacokinetic parameter according to blood drug level-time data.
Result of calculation shows:
Mifepristone Cmax is 1440.30 ± 277.50 (ng/ml) in the mifepristone capsule of the present invention; Tmax is 0.92 ± 0.13 (h); T1/2 (ke)Be 7.31 ± 1.91 (h); AUC 0 → 24Be 13132.08 ± 2165.44 (ng/ml*h): AUC 0-∞Be 13871.57 ± 2167.66 (ng/ml*h);
The Cmax of mifepristone is 429.92 ± 37.13 (ng/ml) in the mifepristone sheet (control formulation); Tmax is 0.71 ± 0.19 (h); T1/2 (ke)Be 5.06 ± 1.01 (h); AUC 0 → 24Be 2723.68 ± 652.05 (ng/ml*h); AUC 0-∞Be 2723.68 ± 652.05 (ng/ml*h).Concrete outcome sees Table 1,2,3.
6 in table 1 is tried the medicine kinetic parameter (the present invention) of mifepristone after the Canis familiaris L. administration
NO Ke (h -1) T 1/2(ke) (h) Tmax (h) Cmax (ng/ml) AUC 0-24 (ng·h·ml -1) AUC 0-∞ (ng·h·ml -1)
A B C D E F Mean SD 0.078 0.12 0.017 0.12 0.083 0.13 0.10 0.026 8.88 5.78 9.76 5.78 8.35 5.33 7.31 1.91 0.75 0.75 1.00 1.00 1.00 1.00 0.92 0.13 1387.33 1116.91 1693.53 1333.93 1851.58 1258.51 1440.30 277.50 10097.64 10634.38 14738.57 14818.33 14067.90 14435.63 13132.08 2165.44 11075.97 11125.13 15758.15 15371.33 14990.91 14907.94 13871.57 2167.66
6 in table 2 is tried the medicine kinetic parameter (control formulation) of mifepristone after the Canis familiaris L. administration
NO Ke (h -1) T 1/2(ke) (h) Tmax (h) Cmax (ng/ml) AUC 0-24 (ng·h·ml -1) AUC 0-∞ (ng·h·ml -1)
A B C D E F Mean SD 0.11 0.16 0.12 0.16 0.12 0.18 0.14 0.029 6.30 4.33 5.78 4.33 5.78 3.85 5.06 1.01 1.00 0.75 0.50 0.75 0.50 0.75 0.71 0.19 391.46 399.04 403.36 442.87 480.00 462.76 429.92 37.13 2043.07 1747.85 3233.67 3062.59 3058.96 3195.92 2723.68 652.05 2043.07 1747.85 3233.67 3062.59 3058.96 3195.92 2723.68 652.05
The capsular relative bioavailability of table 3 mifepristone of the present invention is calculated
NO AUC of the present invention 0-∞(ng·h·ml -1) Control formulation AUC 0-∞(ng·h·ml -1) Relative bioavailability (%)
A B C D E F Mean SD 11075.97 11125.13 15758.15 15371.33 14990.91 14907.94 13871.57 2167.66 2043.07 1747.85 3233.67 3062.59 3058.96 3195.92 2723.68 652.05 542.12 636.50 487.31 501.91 490.07 466.47 520.73 61.99
Above-mentioned main pharmacokinetic parameter is carried out statistical analysis and evaluation of bioequivalence, and the result shows: Cmax, Tmax and the AUC of mifepristone between two kinds of preparations 0-∞Significant significant difference (p＜0.05) is all arranged; The average relative bioavailability of mifepristone is 520.73 ± 61.99 (%) in the mifepristone capsule (the present invention), and 90% of its bioavailability parameter value crediblely is limited to 1378.75～4068.61%.This shows mifepristone capsule of the present invention have taking dose low, absorb fast, blood drug level and the high characteristics of bioavailability.
The antiearly pregnancy clinical effectiveness:
The present invention carries out clinical trial through State Drug Administration's approval.This test is multi-center randomized double research, compares the oral total amount 50mg of gradation mifepristone capsule of the present invention or the commercially available mifepristone tablet of 150mg (matched group), the termination of early pregnancy effect of compatibility 600 μ g misoprostols.(test group) this research observes 240 to (480 example) altogether 3 clinical outpatient services in clinical pharmacology base.
Clinical effectiveness sees the following form:
The effect of two group termination early pregnancies
Stop reason Mifepristone capsule of the present invention (50mg) Commercially available mifepristone tablet (150mg)
Quantity Effective percentage % Quantity Effective percentage %
Artificial abortion 232 97.1 227 94.6
Failure 2 0.8 0 0
Incomplete abortion, the clearing heat in the pericardium 5 2.1 10 4.2
Incomplete abortion, the urgent clearing heat in the pericardium 0 0 3 1.2
From as can be seen above, the present invention reaches same clinical effectiveness with 1/3 dosage 50mg and marketed tablet 150mg, and effective percentage does not have significant difference between the two.
The specific embodiment
Embodiment 1
With mifepristone 2 grams, polyoxyethylene castor oil double glyceride 25 grams, poloxamer 73 grams mix, and stir, and heating for dissolving is made 100 of capsules with the capsule liquid-filling machine, and mifepristone content is 0.02 gram/grain.
Embodiment 2
With mifepristone 3 grams, polyoxyethylene castor oil and certain herbaceous plants with big flowers acid glyceryl laurate ester mixture (1: 1, weight ratio) 24 grams, poloxamer 73 grams mix, and stir heating for dissolving, make 100 of capsules with the capsule liquid-filling machine, mifepristone content is 0.03 gram/grain.
Embodiment 3
With mifepristone 3 grams, polyoxyethylene (6) sorbitan mono-laurate 24 grams, the mixture of polyoxyethylene (40) stearate and poloxamer (1: 1, weight ratio) 73 grams mix, stir, heating for dissolving is made 100 of capsules with the capsule liquid-filling machine, and mifepristone content is 0.03 gram/grain.

Claims (1)

1. the compositions of a mifepristone semi-solid skeleton preparation is characterized in that component and content are: mifepristone 0.5～5wt%, surfactant 1～50wt%, the carrier 45～98.5wt% of semi-solid backbone;
Surfactant is selected from one or more in polyoxyethylene castor oil double glyceride, polyoxyethylene (6) sorbitan mono-laurate, polyoxyethylene mono laurate Pyrusussuriensis ester, polyoxyethylene list oleic acid Pyrusussuriensis ester, Brij30, polyoxyethylene (10) monolaurate, polyoxyethylene castor oil, certain herbaceous plants with big flowers acid glyceryl laurate ester or the caproic acid glyceryl laurate ester;
The carrier of semi-solid backbone is selected from one or more in polyoxyethylene (40) stearate, poloxamer, polyoxyethylene sorbitan monostearate, 12～18 carbon fatty acid glyceride or the propylene glycol stearate.
CNB021368376A 2002-09-05 2002-09-05 Composition of mifepristone semi-solid skeleton preparation Expired - Fee Related CN1255107C (en)

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PCT/CN2003/000741 WO2004022067A1 (en) 2002-09-05 2003-09-03 Semi-solid skeleton composition of mifepristone
AU2003261600A AU2003261600A1 (en) 2002-09-05 2003-09-03 Semi-solid skeleton composition of mifepristone

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EP1987814A1 (en) 2007-04-30 2008-11-05 Exelgyn Mifepristone pharmaceutical compositions and their methods of preparation
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
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.
RU2617536C2 (en) * 2015-07-08 2017-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта" Method of preparing pregnant women for labour induction with premature rupture of membranes in the absence of biological childbirth readiness at full-term period

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WO2004022067A1 (en) 2004-03-18

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