WO2004022067A1 - Composition de squelette semi-solide de mifepristone - Google Patents

Composition de squelette semi-solide de mifepristone Download PDF

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Publication number
WO2004022067A1
WO2004022067A1 PCT/CN2003/000741 CN0300741W WO2004022067A1 WO 2004022067 A1 WO2004022067 A1 WO 2004022067A1 CN 0300741 W CN0300741 W CN 0300741W WO 2004022067 A1 WO2004022067 A1 WO 2004022067A1
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WO
WIPO (PCT)
Prior art keywords
mifepristone
polyoxyethylene
semi
solid skeleton
monolaurate
Prior art date
Application number
PCT/CN2003/000741
Other languages
English (en)
Chinese (zh)
Inventor
Linjin Gu
Liangxin Wu
Original Assignee
Shanghai Institute Of Pharmaceutical Industry
Shenzhen Jifu Industry Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Institute Of Pharmaceutical Industry, Shenzhen Jifu Industry Co., Ltd. filed Critical Shanghai Institute Of Pharmaceutical Industry
Priority to AU2003261600A priority Critical patent/AU2003261600A1/en
Publication of WO2004022067A1 publication Critical patent/WO2004022067A1/fr

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Classifications

    • 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

Definitions

  • composition of mifepristone semi-solid matrix preparation Composition of mifepristone semi-solid matrix preparation
  • the invention relates to a mifepristone preparation.
  • the molecular formula is C 29 H 35 N0 2 and the molecular weight is 429.61.
  • Mifepristone is a receptor-level antiprogestin antagonist with the effects of terminating early pregnancy, anti-implantation, inducing menstruation and promoting cervical maturation. It has been widely used clinically for emergency contraception against early pregnancy and has good effects. New indications for the treatment of uterine fibroids, endometriosis, breast cancer, and depression are also under development.
  • mifepristone As a newer endometrium progesterone receptor antagonist, mifepristone has the advantages of convenient use and good safety effect. When a water-insoluble drug is absorbed by the digestive tract in the body, its absorption rate is usually proportional to its solubility. Mifepristone is a water-insoluble drug, and its absorption rate in the gastrointestinal tract is low after oral administration (absolute biological profit is 30-50%). Therefore, in order to achieve the expected clinical effect, The clinical dose has to be increased, resulting in adverse reactions and expensive problems.
  • Chinese patent CN1111512A anti-early pregnancy drug composition is composed of mifepristone and dicarbinate and the balance of pharmaceutically acceptable carrier to reduce the dose of the main drug and reduce the unfavorable response.
  • Chinese patent CN1218665A high-efficiency mifepristone preparation Chinese patent CN1311000A mifepristone pill and preparation method thereof is a mifepristone-containing pill containing mifepristone and propylene glycol, ethanol, and Tween-20 , Mifepristone solution and gelatin made of auxiliaries such as PEG-400 and gelatin are used as outer wrapping materials. From the current implementation of the above patents, except for CN1218665A, they all have a certain effect, but the clinical effect of the former against early pregnancy is still not ideal (effective rate is about 90%), and the clinical dose of the latter is reduced from 150mg / case. At 75 mg / case, the dose was only reduced by half.
  • the technical problem to be solved by the present invention is to disclose a mifepristone semi-solid framework preparation (Semi Solid Mairix), that is, a substance having a wax-like melting point is added to a medicinal solution, which can be hot-melted at high temperature and solid at room temperature.
  • a mifepristone semi-solid framework preparation (Semi Solid Mairix)
  • a substance having a wax-like melting point is added to a medicinal solution, which can be hot-melted at high temperature and solid at room temperature.
  • it can prevent drug powder from flying up (especially suitable for hormones and anticancer drugs); uniform filling amount and accurate main drug dose; the drug or liquid is dispersed in excipients and air and moisture Isolation is more stable; appropriate adjustment of the prescription can achieve the desired high biological profitability, in order to make the pharmacologically active substance mifepristone better absorbed in the body, to achieve good efficacy and reduce adverse reactions at lower doses .
  • the preparation of the present invention includes-
  • the semi-solid skeleton carrier used in the present invention includes polyethylene glycol, polyoxyethylene (40) stearate, poloxamer, polyoxyethylene sorbitan monostearate, 12-18 carbon fatty acid glycerol One or more of esters or propylene glycol stearate. From the viewpoint of water dispersibility and process, polyoxyethylene sorbitan monostearate or poloxamer is preferable.
  • the main role of the surfactant is to increase the hydrophilicity of mifepristone and promote its absorption in the body.
  • Surfactants can increase the solubility of poorly soluble drugs in water, which is generally considered to be the result of the formation of micelles (micelles) in water by surfactants.
  • the micelle is formed by the lipophilic group of the surfactant inward to form a very small oil droplet (non-polar center region), while the hydrophilic group
  • the clusters are outward (non-ionic hydrophilic groups extend from the surface of the oil droplets into the water phase in a wave-like manner) and form spheroids.
  • micelles can insert solubilizing molecules such as mifepristone with slightly polar molecules into the oil droplets in the micelles with the non-polar portion of the molecules, and the polar portion of the surfactant can extend into the surface of the surfactant. Solubilization occurs between hydrophilic groups.
  • Surfactants have the function of solubilizing lipids at low concentrations. They can dissolve phospholipids in the mucosa of the digestive tract, change the permeability of epithelial cells, and reduce the barrier effect of intestinal mucosal lipids. Therefore, many drugs that are difficult to absorb by passive diffusion are added with surfactants to increase absorption. therefore
  • Surfactants with a higher HLB value can both increase the solubility of mifepristone in water and reduce the barrier effect of intestinal mucosal lipids and increase their absorption in the body.
  • the semi-solid matrix carrier is preferably a matrix with a certain HLB value.
  • it is water-soluble and can be used as a semi-solid dispersion of poorly water-soluble drugs, and has a certain fat-soluble performance.
  • Ketones can also form a low-melting eutectic after mixing, increasing the absorption of the drug in the body.
  • the preparation of the present invention is prepared in such a way that the ingredients are quantitatively mixed in the above proportion, stirred, and heated to make the preparation easier.
  • the capsule liquid filling machine (with styling equipment) can be used to make capsules or other equipment. Drop pills, powders, etc.
  • the stability of the mifepristone semi-solid skeleton preparation prepared according to the present invention is investigated: the product is directly exposed to nakedness at 3000LX, 40 ° C, and 25 ° C RH92.5% in air at room temperature. Compared with the original sample, this product is basically stable for inspection of properties, degradation products, dissolution and content. This product is in the market packaging, 40 ° C, RH75% Accelerate 3 months under the conditions and store at room temperature for 24 months, and observe and determine according to the established quality standard inspection indicators regularly. This product is basically stable.
  • composition of this product uses tablets as a control and distilled water as a medium to measure the dissolution to show the superiority of each component-the mifepristone is formulated into 1% semi-solid skeleton type prescriptions A and B with different components , C, D as the test product, the original tablet as the control, according to the 2000 edition of the Chinese Pharmacopoeia Appendix XC dissolution test method slightly changed the dissolution test: Measure 500ml of degassed distilled water, Inject into each operation container, heat to keep the water temperature at 37 ° C ⁇ 0.5 ° C, accurately weigh 2 g of test sample, add to each of the 6 operation containers, immediately start rotation (100 rpm), and start At 30 minutes, a sample was taken at a specified point and immediately filtered through a double-layer 0.8 m microporous membrane. The filtrate was measured according to the determination method of mifepristone content, and the dissolution percentage was calculated. The results are shown in the table below:
  • the dissolution percentages of the tablets and components A, B, C, and D at 30 minutes were 0, 31.64%, 45.79%, 61.45%, and 81.53%, respectively.
  • the tablets are basically insoluble in distilled water (the dissolution medium in the tablet quality standard is 0.1mol / L hydrochloric acid solution).
  • Component D was the best with a dissolution percentage of 81.53%.
  • the ED50 of the anti-early pregnancy effect of the contents of mifepristone gelatin pills and misoprostol on rats is 62.54 ⁇ 214.25 g / kg, and the 95% confidence limit is 276.44 ⁇ 801.72 ⁇ g / kg, commercially
  • the ED50 of mifepristone tablets is 580.02 ⁇ 214.25 wg / kg (95% confidence limit is 276.44-801.72 g / kg), indicating that the content of mifepristone pellets is stronger for rats than tablets.
  • Anti-early pregnancy effect about 9 times the tablet.
  • Pregnant rats were intragastrically administered with excipients, the contents of the mifepristone capsules of the present invention and the commercially available mifepristone tablets from 6 to 7 am on the d of pregnancy. The embryos were observed at d 14 during the second pregnancy. See Tables A and B. Table A The anti-early pregnancy effect of the contents of the mifepristone capsules of the present invention on rats
  • the semi-solid skeleton-type preparation of the present invention has anti-early pregnancy effect ED 5 in rats. It is 17 times of the commercially available tablet, and the anti-early pregnancy effect of ED 5Q is much stronger than that of the commercially available tablet.
  • Experimental study on the relative bioavailability of mifepristone capsules of the present invention :
  • mifepristone capsules of the present invention containing 150 mg of mifepristone in a single cross-fasted stomach were administered to each other by the same body cross test method, or produced by Zhejiang Xianju Pharmaceutical Co., Ltd.
  • Mifepristone tablets were used as a control preparation, 6 tablets containing 150 mg of mifepristone.
  • the drug concentration in blood paddles at different times was determined by high performance liquid chromatography. Based on the blood concentration-time data, the main pharmacokinetics were obtained. parameter.
  • Mifepristone Cmax in the mifepristone capsule of the present invention is 1403.30 ⁇ 277.50 (ng / ml); Tmax is 0.92 ⁇ 0.13 (h); tl / 2 (ke) is 7.31 ⁇ 1.91 (h); AU- 24 is 13132.08 ⁇ 2165.44 (ng / ml * h): AUC is 13871.57 ⁇ 2167.66 (ng / ml * h);
  • the Cmax of mifepristone in mifepristone tablets (control preparation) is 429.92 ⁇ 37.13 (ng / ml);
  • Tmax is 0.71 ⁇ 0.19 (h); tl / 2 ( ke ) is 5.06 ⁇ 1.01 (h); AUC 0 _ 24 is 2723.68 ⁇ 652.05 (ng / ml * h); 8 110). ⁇ is 2273.68 ⁇ 652.05 (ng / ml * h).
  • the invention has been approved for clinical trials by the State Drug Administration. This trial is a multi-center, randomized, double-blind study comparing the total oral administration of 50 mg of mifepristone capsules of the present invention or 150 mg of commercially available mifepristone tablets (control group), which is compatible with 600 misoprostol to terminate early pregnancy .
  • the present invention achieves the same clinical effect with a 1/3 dose of 50 mg and a commercially available tablet of 150 mg, and there is no significant difference between the effective rates.

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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

La présente invention concerne une composition de squelette semi-solide. La composition selon l'invention comprend de 0,5 à 5 % en poids de mifépristone, de 1 à 50 % en poids de tensioactif avec un rapport hydrophile-lipophile (HLB) supérieur à 12 et de 45 à 98,5 % en poids d'un support de squelette semi-solide. La composition présente une bonne capacité de lixiviation, un puissant effet de résistance aux grossesses précoces, une valeur ED50 chez le rat qui est égale à 17 fois celle du comprimé mis sur la marché et une biodisponibilité chez le chien qui est égale à 5 fois celle du comprimé mis sur le marché. Les études cliniques en double aveugle indiquent que la présente invention produit un effet clinique trois fois supérieur à celui du comprimé mis sur le marché. La capsule de mifépristone selon la présente invention possède l'avantage d'un faible dosage, d'un effet négatif moins important et d'une biodisponibilité élevée.
PCT/CN2003/000741 2002-09-05 2003-09-03 Composition de squelette semi-solide de mifepristone WO2004022067A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003261600A AU2003261600A1 (en) 2002-09-05 2003-09-03 Semi-solid skeleton composition of mifepristone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB021368376A CN1255107C (zh) 2002-09-05 2002-09-05 米非司酮半固体骨架制剂的组合物
CN02136837.6 2002-09-05

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WO2004022067A1 true WO2004022067A1 (fr) 2004-03-18

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AU (1) AU2003261600A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1990044A1 (fr) 2007-04-30 2008-11-12 Exelgyn Compositions pharmaceutiques de mifepristone et leurs procédé de préparation
US20150164917A1 (en) * 2012-06-21 2015-06-18 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
RU2617536C2 (ru) * 2015-07-08 2017-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта" Способ подготовки к родовозбуждению беременных женщин с преждевременным излитием околоплодных вод на фоне отсутствия биологической готовности к родам при доношенном сроке

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100342856C (zh) * 2003-04-10 2007-10-17 上海医药工业研究院 达那唑半固体骨架制剂的组合物
CN102107007B (zh) * 2011-01-28 2012-11-07 广州朗圣药业有限公司 甾体类抗孕激素组合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1218665A (zh) * 1997-12-03 1999-06-09 上海市计划生育科学研究所 高效米非司酮制剂、其制备方法和用途
CN1231177A (zh) * 1998-04-08 1999-10-13 上海市计划生育科学研究所 新颖的避孕药物组合物及其制备方法
CN1311000A (zh) * 2000-02-29 2001-09-05 上海华联制药有限公司 米非司酮胶丸及其制备方法
CN1087170C (zh) * 1995-03-11 2002-07-10 上海市计划生育科学研究所 抗早孕药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1087170C (zh) * 1995-03-11 2002-07-10 上海市计划生育科学研究所 抗早孕药物组合物
CN1218665A (zh) * 1997-12-03 1999-06-09 上海市计划生育科学研究所 高效米非司酮制剂、其制备方法和用途
CN1231177A (zh) * 1998-04-08 1999-10-13 上海市计划生育科学研究所 新颖的避孕药物组合物及其制备方法
CN1311000A (zh) * 2000-02-29 2001-09-05 上海华联制药有限公司 米非司酮胶丸及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1990044A1 (fr) 2007-04-30 2008-11-12 Exelgyn Compositions pharmaceutiques de mifepristone et leurs procédé de préparation
US20150164917A1 (en) * 2012-06-21 2015-06-18 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
RU2617536C2 (ru) * 2015-07-08 2017-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта" Способ подготовки к родовозбуждению беременных женщин с преждевременным излитием околоплодных вод на фоне отсутствия биологической готовности к родам при доношенном сроке

Also Published As

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CN1255107C (zh) 2006-05-10
AU2003261600A8 (en) 2004-03-29
AU2003261600A1 (en) 2004-03-29
CN1408356A (zh) 2003-04-09

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