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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Prior art keywords
mifepristone
polyoxyethylene
semi
solid skeleton
monolaurate
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PCT/CN2003/000741
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English (en)
French (fr)
Inventor
Linjin Gu
Liangxin Wu
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Shanghai Institute Of Pharmaceutical Industry
Shenzhen Jifu Industry Co., Ltd.
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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/zh

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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

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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Description

米非司酮半固体骨架制剂的组合物
技术领域
本发明涉及一种米非司酮制剂。
背景技术
米非司酮，其英文名称为 mifepristone, 其化学名称为 11 β -[4-(N,N- 二甲胺基)苯基] -17 β -¾¾-17 α -(1 丙炔基)雌 -4，9-二烯 -3-酮 1,3， 其 结构式如下：
Figure imgf000002_0001
分子式为 C29H35N02, 分子量为 429.61。
中国专利 86102502公开了米非司酮及其制备方法。 米非司酮是一种 受体水平抗孕激素拮抗剂， 具有终止早孕、 抗着床， 诱导月经及促宫颈 成熟的作用。 在临床上已被广泛用于抗早孕紧急避孕， 并且具有良好的 效果。 新的适应症治疗子宫肌瘤、 子宫内膜异位症、 乳腺癌、 抑郁症等 也在开发研究之中。
作为较新颖的子宫内膜孕酮受体拮抗剂， 米非司酮具有使用方便、 安全效果好的优点。 由于水难溶性药物被体内消化道吸收时， 通常其吸 收率和其溶解度成正比。 米非司酮是水不溶性药物， 口服后在胃肠道的 吸收率较低（绝对生物利度为 30〜50%)， 因此， 为达到预期的临床疗效， 不得不加大临床剂量， 而产生不良反应以及价格昂贵的问题。
为了解决以上问题， 许多专利披露了各自的技术， 以克服口服吸收 差的缺点， 以期能达到提高生物利度、 降低剂量、减少不优反应的目的。 如： 中国专利 CN1111512A抗早孕药物组合物以米非司酮和双炔失碳酯 及余量药学上可接受的载体组成复方以减少主药剂量， 降低不优反应。 中国专利 CN1218665A高效米非司酮制剂， 中国专利 CN1311000A米 非司酮胶丸及其制备方法为一种含有米非司酮的胶丸， 内含米非司酮以 及丙二醇、 乙醇、 吐温 -20、 聚乙二醇 -400 等辅料制成的米非司酮溶液 和明胶作为外包裹材料制成。 上述专利从目前实施情况来看， 除 CN1218665A夕卜， 都有一定的疗效， 但前者抗早孕临床效果还不太理想 (有效率 90%左右）， 后者的抗早孕临床剂量从 150mg/例降为 75mg/例， 也仅降低了一半剂量。
综上所述， 目前还没有十分理想的米非司酮制剂， 因此研究开发一 种新的米非司酮制剂， 是医药领域十分迫切的任务。
发明内容
本发明需要解决的技术问题是公开一种米非司酮半固体骨架制剂 (Semi Solid Mairix), 即在药液中加入具有蜡状熔点样的物质， 在高温 时能够热熔， 室温时为固体， 与传统的粉末颗粒相比， 它可以避免药物 粉末飞扬 （尤其适用于激素与抗癌药）； 装填量均匀， 主药剂量准确； 药物或药液分散于赋形剂中与空气和湿气隔绝， 因而较稳定； 适当调整 处方， 可获得所期望的高生物利度， 以期使药理活性物质米非司酮在体 内的吸收更好， 在更低的剂量下取得好的疗效并减少不良反应。 本发明的制剂包括- 米非司酮 0.5〜5% (重量）
HLB (亲水亲油平衡值） 12以上的表面活性剂 1~50% (重量） 半固体骨架的载体 45〜98.5% (重量） 符合上述条件的表面活性剂包括聚氧乙烯蓖麻油双甘油酯、 聚氧乙 烯 （6) 失水山梨醇单月桂酸酯 （司盘 20) 等失水山梨醇脂肪酸酯 （司 盘）、 聚氧乙烯单月桂酸山梨酯、 聚氧乙烯单油酸山梨酯等聚氧乙烯脂 肪酸山梨酯 （吐温）、 聚氧乙烯月桂醇醚等的聚氧乙烯烷基醚、 聚氧乙 烯 （10) 单月桂酸酯等的聚乙二醇脂肪酸酯、 聚氧乙烯蓖麻油、 葵酸月 桂酸甘油酯、 己酸月桂酸甘油酯等混合脂肪酸甘油酯以及它们中两种以 上组成的混合物。 从水分散性和安全方面来看， 可优选葵酸月桂酸甘油 酯和聚氧乙烯单月桂酸山梨酯。
本发明中所用的半固体骨架的载体包括聚乙二醇、 聚氧乙烯 （40) 硬脂酸酯、 泊洛沙姆、 聚氧乙烯山梨醇酐单硬脂酸酯、 12〜18 碳脂肪酸 甘油酯或硬脂酸丙二醇酯中的一种或一种以上。 从水分散性以及工艺上 考虑， 可优选聚氧乙烯山梨醇酐单硬脂酸酯或泊洛沙姆。
所说的表面活性剂的主要作用是增加米非司酮的亲水性， 促进其在 体内的吸收， 其亲水亲油平衡值 HLB 值越大， 其亲水性也越大， 作用 也就更强。
表面活性剂所以能增大难溶性药物在水中的溶解度， 一般认为是由 于表面活性剂在水中形成胶束 （胶团） （Micelles) 结果。 胶团是由表面 活性剂的亲油基团向内形成一极小的油滴 （非极性中心区）， 而亲水基 团则向外 （非离子型的亲水基团则从油滴表面如波状似的向四周伸入水 相中） 而成球状体。
现今认为， 胶团可将增溶质如米非司酮稍带极性的分子以其分子的 非极性部分***胶团中的油滴中， 其极性部分则伸入水中的表面活性剂 的亲水基之间而产生增溶作用。
表面活性剂在低浓度时有溶解脂质的作用， 能溶解消化道粘膜的磷 脂质而改变上皮细胞的通透性， 降低肠粘膜类脂体的屏障作用。 故许多 本来按被动扩散难以吸收的药物， 加入表面活性剂而使吸收增加。 因此
HLB 值较高的表面活性剂既能增加米非司酮在水中的溶解度， 又能降 低肠粘膜类脂体的屏障作用而增加其在体内的吸收。
所说的半固体骨架载体以具有一定的 HLB 值的基质为好， 一方面 它具有水溶性， 能作为水难溶性药物的半固体分散体， 且又有一定的脂 溶性能， 与米非司酮混合后还能形成低熔点的共融物， 增加药物在体内 的吸收。
本发明的制剂是这样制备的- 将各成分按上述比例定量混合， 搅拌， 加温可使配制更易进行， 用 胶囊液体灌装机（有定型设备）可制成胶囊、也可用其他设备制成滴丸、 粉剂等。
对本发明所述制得的米非司酮半固体骨架制剂的稳定性进行考察： 本品除去外包装直接裸置于光照 3000LX、 40°C，室温空气中 25°C RH92.5%条件下 10 天， 与原始样品对比， 进行性状、 降解产物检查、 溶出度、含量测定等，本品基本稳定。本品在上市包装下， 40°C、 RH75% 条件下加速 3个月及室温储藏 24个月并定期按制订的质量标准考察指 标观察测定， 本品基本稳定。
本品各组成物以片剂为对照、 以蒸馏水作介质测定溶出度， 以显示 各组分的优越性- 将米非司酮配成 1%的不同组分的半固体骨架型处方 A、 B、 C、 D 作为试验品， 以原片剂为对照物， 按照 2000版中国药典附录 XC溶出 度测定法中第二法稍作改变后进行溶出度试验： 量取经过脱气处理的蒸 馏水 500ml， 注入每个操作容器内， 加温使水温保持在 37°C ±0.5°C， 精密称取供试样品 2克， 分别加入 6个操作容器内， 立即启动旋转（100 转 /分）， 并开始计时， 至 30分钟时， 在规定点取样， 并立即经双层 0.8 m微孔滤膜滤过， 取续滤液按米非司酮含量测定方法进行测定， 计算 溶出百分率， 结果见下表：
片剂与各组分的溶出百分率 （％， 30分钟)
Figure imgf000006_0001
从表中可以看出， 片剂以及组分 A、 B、 C、 D在 30分钟时溶出百 分率分别为 0、 31.64%、 45.79%、 61.45%和 81.53%。 说明片剂在蒸馏 水中基本不溶出 （片剂质量标准中的溶出介质为 0.1mol/L盐酸液）。 组 分 D最好， 溶出百分率为 81.53%。
动物药效学试验: 天 1次， 共 3次。 妊娠 d 14天观察胚胎情况， 见下表:
米非司酮胶丸内容物合并米索前列醇对大鼠的抗早孕作用
Figure imgf000007_0001
市售米非司酮片剂合并米索前列醇对大鼠的抗早孕作用
Figure imgf000007_0002
由表可见， 米非司酮胶丸内容物合并米索前列醇对大鼠的抗早孕作 用的 ED50为 62.54±214.25 g/kg, 95%可信限为 276.44~801.72 μ g/kg, 市售米非司酮片剂的 ED50 为 580.02 ± 214.25 w g/kg， （95%可信限为 276.44-801.72 g/kg), 表明米非司酮胶丸内容物对大鼠较片剂有较强 的抗早孕作用， 约为片剂的 9倍。
妊娠大鼠于妊娠 d 6-7上午灌胃给于辅料、 本发明的米非司酮胶囊 内容物及市售米非司酮片剂， 每天 1次， 共 2次妊娠 d 14观察胚胎情 况。 见表 A和表 B。 表 A本发明米非司酮胶囊内容物对大鼠的抗早孕作用
Figure imgf000008_0001
经计算机用 Bliss方法计算： 米非司酮胶囊内容物对大鼠抗早孕作用 的 ED5。为 126.6 g/kg, 95%可信限为 76.4-209.7 g/kg。
表 B市售米非司酮片剂对大鼠的抗早孕作用
Figure imgf000008_0002
经计算机用 Bliss方法计算： 米非司酮片剂对大鼠抗早孕作用的 ED: 为 2163ug/kg, 95%可信限为 1429-3274 μ g/kg。
由表 A、 B可见， 本发明米非司酮胶囊内容物和市售片剂对大鼠 抗早孕的 ED5Q分别为 126.6y g/kg和 2163 ί^/1 , 本发明米非司酮胶囊 内容物对大鼠的抗早孕作用较片剂强， 约为片剂的 17倍。
由上可看出， 本发明半固体骨架型制剂对大鼠抗早孕作用 ED5。是 市售片剂的 17倍， 比米非司酮胶丸对大鼠抗早孕作用 ED5Q是市售片剂 的 9倍要强得多。 本发明米非司酮胶囊动物相对生物利用度试验研究：
以家犬 6只为试验对象， 采用同体交叉试验方法， 分别单次交叉空 腹灌胃给本发明的米非司酮胶囊， 含米非司酮 150mg， 或以浙江仙居制 药股份有限公司生产的米非司酮片剂为对照制剂， 6 片， 含米非司酮 150mg,采用高效液相色谱法测定不同时间血桨中药物浓度， 根据血药浓 度-时间数据,求得了主要药代动力学参数。
计算结果显示：
本发明米非司酮胶囊中米非司酮 Cmax为 1440.30±277.50 (ng/ml)； Tmax为 0.92±0.13(h); tl/2 (ke)为 7.31 ± 1.91(h); AU — 24为 13132.08士 2165.44(ng/ml*h): AUC 为 13871.57±2167.66(ng/ml*h);
米非司酮片（对照制剂）中米非司酮的 Cmax为 429.92±37.13(ng/ml);
i |
Tmax为 0.71 ±0.19(h); tl/2(ke)为 5.06 ± 1.01(h); AUC0_24 为 2723.68士 652.05(ng/ml*h);八110).∞为 2723.68±652.05(ng/ml*h)。具体结果见表 1、 2、 3。
6只受试狗给药后米非司酮的药动力学参数（本发明)
Ke T1/2(ke) Tmax Cmax AUC0_24 AUC0.∞
NO
(h-1) (h) (h) (ng/ml) (ng · l · ml"1)
A 0.078 8.88 0.75 1387.33 10097.64 11075.97
B 0.12 5.78 0.75 1116.91 10634.38 11125.13
C 0.017 9.76 1.00 1693.53 14738.57 15758.15
D 0.12 5.78 1.00 1333.93 14818.33 15371.33
E 0.083 8.35 1.00 1851.58 14067.90 14990.91
F 0.13 5.33 1.00 1258.51 14435.63 14907.94
Mean . 0.10 7.31 0.92 1440.30 13132.08 13871.57
SD 0.026 1.91 0.13 277.50 2165.44 2167.66 表 2 6只受试狗给药后米非司酮的药动力学参数 （对照制剂)
Ke T1/2(ke) Tmax Cmax AUC0— 24 AUC0.∞ ~
(h-1) (h) (h) (ng/ml) (ng · h · ml—1) (ng . h · ml—1) 0.11 6.30 1.00 391.46 2043.07 2043.07
4.33
EFDC 0.16 0.75 399.04 1747.85 1747.85
AB
0.12 5.78 0.50 403.36 3233.67 3233.67
0.16 4.33 0.75 442.87 3062.59 3062.59
0.12 5.78 0.50 480.00 3058.96 3058.96
Figure imgf000010_0001
对上述主要药物动力学参数进行统计分析和生物等效性评价， 结果 表明： 两种制剂间米非司酮的 Cmax、 Tmax和 AUCQ—∞均有显著的统计 学差异 (p<0.05); 米非司酮胶囊 （本发明） 中米非司酮的平均相对生物 利用度为 520.73 ± 61.99(%)， 其生物利用度参数值的 90%可信限为 1378.75〜4068.61%。 由此可以看出本发明的米非司酮胶囊具有服用剂 量低、 吸收快、 血药浓度和生物利用度高的特点。
抗早孕临床结果：
本发明经国家药品监督局批准进行临床试验。 本试验为多中心随机 双盲研究， 比较分次口服总量 50mg本发明的米非司酮胶囊或 150mg市 售米非司酮片剂 （对照组）， 配伍 600 米索前列醇的终止早孕作用。
(试验组）本研究在 3个临床药理基地临床门诊共观察 240对（480例）。 临床结果见下表:
两组终止早孕的效果
Figure imgf000011_0001
从以上可以看出， 本发明以 1/3剂量 50mg与市售片剂 150mg达到 同样的临床效果， 有效率两者间无显著差异。
具体实施方式
实施例 1
将米非司酮 2克， 聚氧乙烯蓖麻油双甘油酯 25克， 泊洛沙姆 73克 混合， 搅拌均匀， 加热溶解， 用胶囊液体灌装机制成胶囊 100粒， 米非 司酮含量为 0.02克 /粒。
实施例 2
将米非司酮 3克， 聚氧乙烯蓖麻油与葵酸月桂酸甘油酯混合物 （1 : 1， 重量比） 24克， 泊洛沙姆 73 克混合， 搅拌均匀， 加热溶解， 用胶 囊液体灌装机制成胶囊 100粒， 米非司酮含量为 0.03克 /粒。
实施例 3
将米非司酮 3克， 聚氧乙烯 （6) 失水山梨醇单月桂酸酯 24克， 聚 氧乙烯 （40 ) 硬脂酸酯与泊洛沙姆的混合物 （1 : 1， 重量比） 73 克混 合， 搅拌均匀， 加热溶解， 用胶囊液体灌装机制成胶囊 100粒， 米非司 酮含量为 0.03克 /粒。

Claims

权利要求书
1. 一种米非司酮半固体骨架制剂的组合物， 其特征在于组分和含 量包括： 米非司酮 0.5〜5wt%， HLB> 12 以上的表面活性剂 l~50wt%， 半固体骨架的载体 45~98.5wt%。
2. 根据权利要求 1 所述的组合物， 其特征在于所述及的表面活性 剂包括聚氧乙烯蓖麻油双甘油酯、 聚氧乙烯 （6) 失水山梨醇单月桂酸 酯 （司盘 20)、 聚氧乙烯单月桂酸山梨酯、 聚氧乙烯单油酸山梨酯、 聚 氧乙烯月桂醇醚、 聚氧乙烯 （10) 单月桂酸酯、 聚氧乙烯蓖麻油、 葵酸 月桂酸甘油酯或己酸月桂酸甘油酯中的一种或一种以上。
3. 根据权利要求 2 所述的组合物， 其特征在于所述及的表面活性 剂为葵酸月桂酸甘油酯和聚氧乙烯单月桂酸山梨酯。
4. 根据权利要求 1 所述的组合物， 其特征在于所述及的半固体骨 架的载体包括聚乙二醇、 聚氧乙烯 （40) 硬脂酸酯、 泊洛沙姆、 聚氧乙 烯山梨醇酐单硬脂酸酯、 12〜18 碳脂肪酸甘油酯或硬脂酸丙二醇酯中的 一种或一种以上。
5. 根据权利要求 4所述的组合物， 其特征在于所述及的半固体骨 架的载体为聚氧乙烯山梨醇酐单硬脂酸酯或泊洛沙姆。
PCT/CN2003/000741 2002-09-05 2003-09-03 Composition de squelette semi-solide de mifepristone WO2004022067A1 (fr)

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EP1990044A1 (en) 2007-04-30 2008-11-12 Exelgyn Mifepristone pharmaceutical compositions and their methods of preparation
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

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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

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Publication number Priority date Publication date Assignee Title
EP1990044A1 (en) 2007-04-30 2008-11-12 Exelgyn Mifepristone pharmaceutical compositions and their methods of preparation
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

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