口服天然黄体酮给药系统的设计
|
摘要
黄体酮属天然孕激素类药,口服后易在胃、肠、肝等多个组织代谢,首过效应强、口服生物利用度低且个体差异大,临床常用注射给药。但黄体酮大多需长期用药,注射给药给患者带来了一定困难,脂质体由于磷脂双分子层形成的囊泡结构,口服后可有效地保护药物不被酶解,提高药物体内外稳定性,促进药物吸收,提高药物生物利用度。本文将孕激素类药物天然黄体酮制成前体脂质体,期望利用脂质体的特点,促进黄体酮吸收,避免体内代谢,提高生物利用度,从而为黄体酮口服制剂的开发奠定理论基础。
本文利用新型前体脂质体制备方法制备了黄体酮前体脂质体,对黄体酮前体脂质体的处方设计、理化性质、胃肠液中的生物稳定性、急性毒性、体外吸收、体内过程及首过效应进行了全面深入的研究,黄体酮前体脂质体的研究未见国内报道。
在黄体酮前体脂质体的处方优选中,采用单因素考察和三元相图优选处方。在此基础上对药脂比进行优选,最终确定前体脂质体处方。通过急性毒性试验考察了黄体酮前体脂质体的急性毒性,结果黄体酮前体脂质体毒性较小,半数致死量小于市售微粉化黄体酮胶丸。通过影响因素实验和加速实验,证明黄体酮前体脂质体对光及温度均敏感,前体脂质体宜在阴凉干燥处保存。通过HPLC法测定黄体酮前体脂质体的含量。通过透射电镜和扫描电镜两种方法观察脂质体的形态,并对空白脂质体和含药脂质体的形态进行比较,确定了脂质体为多层脂质体的形态。通过黄体酮脂质体粒径、电位值测定,证实黄体酮脂质体粒径为103.7nm、粒度分布较窄,脂质体荷负电,ζ电位为-88.9mv。通过葡聚糖凝胶柱层析法测定脂质体的包封率,结果脂质体的包封率达54.95±9.98%。通过影响包封率的因素考察,表明药脂比、稀释倍数均影响脂质体的包封率。通过对前体脂质体在室温及4℃的渗漏率进行考察,发现脂质体在4℃下较稳定。通过对脂质体在人工胃液、人工肠液及大鼠胃内容物、不同肠段内容物中的稳定性考察,结果证实脂质体在人工胃肠液及大鼠胃内容物中,保护作用不强,而在大鼠十二指肠、结肠内容物中保护作用较强,表明脂质体在体内能保护黄体酮避免被肠道降解。
在此基础上,建立了Caco-2细胞模型,从细胞水平初步研究了黄体酮及黄体酮脂质体的转运及转运机制,结果表明黄体酮属生物药剂学分类系统中的Ⅱ类药物,黄体酮的吸收和分泌过程均受到某种载体蛋白的介导,为主动转运方式,表观渗透系数P_(app(BL-AP))＞P_(app(AP-BL)),P-gp抑制剂的存在会增加吸收,提示P-糖蛋白存在。P-糖蛋白又称“药泵”,它可能量依赖性的将细胞内药物泵出到细胞外,抑制P-糖蛋白的表达可能增加药物吸收。而黄体酮脂质体可通过改变黄体酮转运机制,促进黄体酮跨膜转运,打开细胞紧密连接、通过胞间转运,从而有效提高黄体酮的吸收,MTT实验结果表明黄体酮脂质体在1:250倍稀释时对细胞毒性较小。
大鼠灌胃黄体酮脂质体,研究了黄体酮脂质体的体内药物动力学并与市售微粉化黄体酮胶丸作一对比,计算相对生物利用度。采用灵敏度高且临床常用的放射免疫分析方法测定体内黄体酮含量,采用口服交叉给药避免黄体酮口服的个体差异,采用摘除大鼠卵巢避免内源性黄体酮的干扰,采用颈静脉插管术进行血样收集。结果黄体酮脂质体体内药动学行为符合二室模型,与对照组相比,AUC值有显著性差异,生物利用度明显增加,相对生物利用度为289.19%。
采用三种不同给药途径给药,测定黄体酮脂质体的首过效应,结果黄体酮脂质体在实验条件下,约49.49%的黄体酮于首过肝脏时被代谢,约26.00%的黄体酮被胃肠道代谢;静脉给药后黄体酮脂质体较对照组有更大的生物利用度,体内清除率降低。因此认为黄体酮制成脂质体后能有效促进黄体酮吸收,延长黄体酮在体内的驻留时间,提高黄体酮的生物利用度。
为了更有效地避免黄体酮在体内的代谢,进一步提高黄体酮的生物利用度。本文尝试对黄体酮脂质体用壳聚糖进行表面修饰,并测定了修饰脂质体的理化性质。结果脂质体经修饰后,包封率有所降低,脂质体荷正电,修饰脂质体在大鼠胃液中稳定性明显提高,生物利用度明显增加,初步证明本法形成的黄体酮脂质体表面修饰的可行性。
本文对黄体酮前体脂质体的体内外性质进行了一系列研究,对本法形成的脂质体的吸收机理、体内过程及首过效应进行了评价,为口服天然黄体酮前体脂质体制剂的进一步开发和应用奠定了基础。
As the female steroidal hormones,progesterone has been found to metabolize quickly and extensively after orally administrated,which leads to its poor and variable bioavailability,so progesterone is normally administrated by intramuscular route, however,local pain at the injection site is not insignificant and becomes an increasingly important issue as progesterone administration is prolonged.Liposome is one of the fastest growing drug delivery systems,for the delivery of sensitive molecules/compounds such as proteins and hormone,liposome could protect the incorporated agents from degradation,increase the absorption and bioavailability of drugs.In our article,a new kind of progesterone proliposome was made.After orally administrated or mixed with water,the liposome could be formed and the properties of progesterone liposome for improving absorption and protection against metabolism were determined.
At first,progesterone liposome was made by a new kind of proliposome method invented in our laboratories,and the prescription of liposome was optimized,and then the properties including morphology,particle size,protective effect in gastric and intestinal contents,acute toxicity,the absorption in vitro,the bioavailability in vivo and the first-pass effect were determined.There was not such report about progesterone liposome in china.
To optimize the prescription of progesterone proliposome,the single factor experiment and ternary phase diagram were used,and the ratio of drug and lecithin was determined. After proliposome was made,the acute toxicity was determined and the result demonstrated that progesterone liposome was safe with a low toxicity to mice and the LD50 was less than micronized progesterone soft capsule.The stability of liposome was observed through the stress testing and accelerated testing,the results showed that liposome was susceptive to temperature and light,so the liposome should be stored in shady and cool place.
During the determination of entrapment efficiency,High performance liquid chromatography was used to determine the contents of progesterone.The transmission electron microphotography and scanning electron microphotography was used to observe the morphology of progesterone liposome and blank liposome,the results showed the liposome was round with multilayer.The particle sizes and zeta potential of liposome were determined by using the nano-particle sizer,the results demonstrated that the average particle size of liposome was 103.7nm and zeta potential was -88.9mv.The gel filtration chromatography method was established to determine the entrapment efficiency of liposome,and then the influencing factors of entrapment efficiency were studied.The results showed that the entrapment efficiency of liposome was 54.95±9.98%and the ratio of drug and lecithin,diluted times might take an effect on the entrapment efficiency.The leakage rate of liposome at room temperature and 4~C were also studied through the determination of entrapment efficiency,and a low leakage rate in 4℃was observed. Furthermore,progesterone liposome was compared with progesterone liposome made by film evaporation method.The results indicated that the morphology of two kinds of liposome was same,but the entrapment efficiency of liposome made by our method was higher than the other,and the particle size of the former was lower than the latter,which the liposome made by our method was better than that made by film evaporation method. All the results indicated that progesterone liposome could be formed with our method.
To study the protective of liposome against degradation,a method in vitro was established and the residual contents of progesterone liposome versus time after mixed respectively with the artificial gastric juice,artificial intestinal juice or the grastric and intestinal contents of rats were determined.The results indicated that liposome could protect effectively progesterone against the trypsin when it was mixed with the duodenum and colon contents of rats.However,the results were not obvious when liposome was mixed with the other contents as above,because the conditions of intestinal contents was more like the true conditions than the artificial intestinal juice,it could be believed that the liposome could protect effectively progesterone against degradation at intestinal contents when taken orally.
A good absorption model in vitro,Caco-2 cell model,was established in our laboratory, and then the transport of liposome was determined after Caco-2 cell grew for up to twenty-one days and TEER was above 300Ω·cm~2.The results indicated progesterone belonged toⅡtype of drugs in BCS and its transport was active transport.The P_(app) at basolateral to apical direction was higher than that at apical to basolateral direction,and the P-gp inhibitor could improve the accumulative transport flux,which indicated there was P-glycoprotein at basolateral to apical direction.P-glycoprotein could act as a "drug pump" which could pump the drug out of the cells when the drug was absorped.On the other hand,progesterone liposome could improve the drug absorption through facilitating the transcellular transport and opening of tight junction to allow the paracellular pathway. Lastly,the cell toxicity of progesterone and progesterone liposome was determined through MTT experiments,the results showed that progesterone liposome had a little cell toxicity when diluted into 250 times with water.
The pharmacokinetics of progesterone liposome in rats removed ovaries was studied and compared with micronized progesterone soft capsule,and the relative bioavailability was calculated.The radioimmunoassay was used to determine the drug contents during the experiment.Furthermore,cross-over design was used in order to avoid the individual difference.The results indicated that the plasma concentration-time curves for progesterone liposome and micronized progesterone soft capsule fit two compartment open model after intragastric administration to the rats,there was significant difference in AUC between liposome and micronized progesterone,which suggested that liposome had higher bioavailability than micronized progesterone,the relative bioavailability is 289.19%.
It was also studied about the first-pass effect in rats of liposome through three administration route:intragastric administration,caudal injection and hepatic portal injection.The results demonstrated that in liposome group there were 49.49%drugs metabolized by liver and 26.00%drugs of total drugs metabolized by gastric and intestine. When administrated through the caudal injection,the bioavailability of liposome is higher than micronized progesterone soft capsule and the clearance of the former is less than the latter.All those results indicated progesterone liposome could improve the bioavailability of progesterone through improving the absorption and protecting progesterone against metabolism.
Moreover,in order to protect ulteriorly against metabolism in vivo and improve ulteriorly the bioavailability,liposome was tried to modify with chitosan,and the properties of chitosan modified liposome was determined and compared with liposome. The results indicated that the entrapment efficiency of chitosan modified liposome was lower than the liposome,the zeta potential of chitosan modified liposome was positive. All that results indicated that the chitosan modified liposome had been formed.
In our article,the feasibility of progesterone liposome was evaluated through the determination of liposome properties,and the absorption mechanism,the pharmaco- kinetics in vivo,and then the first-pass effect was studied.The results would lay a foundation for the development of progesterone proliposome.
本文利用新型前体脂质体制备方法制备了黄体酮前体脂质体,对黄体酮前体脂质体的处方设计、理化性质、胃肠液中的生物稳定性、急性毒性、体外吸收、体内过程及首过效应进行了全面深入的研究,黄体酮前体脂质体的研究未见国内报道。
在黄体酮前体脂质体的处方优选中,采用单因素考察和三元相图优选处方。在此基础上对药脂比进行优选,最终确定前体脂质体处方。通过急性毒性试验考察了黄体酮前体脂质体的急性毒性,结果黄体酮前体脂质体毒性较小,半数致死量小于市售微粉化黄体酮胶丸。通过影响因素实验和加速实验,证明黄体酮前体脂质体对光及温度均敏感,前体脂质体宜在阴凉干燥处保存。通过HPLC法测定黄体酮前体脂质体的含量。通过透射电镜和扫描电镜两种方法观察脂质体的形态,并对空白脂质体和含药脂质体的形态进行比较,确定了脂质体为多层脂质体的形态。通过黄体酮脂质体粒径、电位值测定,证实黄体酮脂质体粒径为103.7nm、粒度分布较窄,脂质体荷负电,ζ电位为-88.9mv。通过葡聚糖凝胶柱层析法测定脂质体的包封率,结果脂质体的包封率达54.95±9.98%。通过影响包封率的因素考察,表明药脂比、稀释倍数均影响脂质体的包封率。通过对前体脂质体在室温及4℃的渗漏率进行考察,发现脂质体在4℃下较稳定。通过对脂质体在人工胃液、人工肠液及大鼠胃内容物、不同肠段内容物中的稳定性考察,结果证实脂质体在人工胃肠液及大鼠胃内容物中,保护作用不强,而在大鼠十二指肠、结肠内容物中保护作用较强,表明脂质体在体内能保护黄体酮避免被肠道降解。
在此基础上,建立了Caco-2细胞模型,从细胞水平初步研究了黄体酮及黄体酮脂质体的转运及转运机制,结果表明黄体酮属生物药剂学分类系统中的Ⅱ类药物,黄体酮的吸收和分泌过程均受到某种载体蛋白的介导,为主动转运方式,表观渗透系数P_(app(BL-AP))＞P_(app(AP-BL)),P-gp抑制剂的存在会增加吸收,提示P-糖蛋白存在。P-糖蛋白又称“药泵”,它可能量依赖性的将细胞内药物泵出到细胞外,抑制P-糖蛋白的表达可能增加药物吸收。而黄体酮脂质体可通过改变黄体酮转运机制,促进黄体酮跨膜转运,打开细胞紧密连接、通过胞间转运,从而有效提高黄体酮的吸收,MTT实验结果表明黄体酮脂质体在1:250倍稀释时对细胞毒性较小。
大鼠灌胃黄体酮脂质体,研究了黄体酮脂质体的体内药物动力学并与市售微粉化黄体酮胶丸作一对比,计算相对生物利用度。采用灵敏度高且临床常用的放射免疫分析方法测定体内黄体酮含量,采用口服交叉给药避免黄体酮口服的个体差异,采用摘除大鼠卵巢避免内源性黄体酮的干扰,采用颈静脉插管术进行血样收集。结果黄体酮脂质体体内药动学行为符合二室模型,与对照组相比,AUC值有显著性差异,生物利用度明显增加,相对生物利用度为289.19%。
采用三种不同给药途径给药,测定黄体酮脂质体的首过效应,结果黄体酮脂质体在实验条件下,约49.49%的黄体酮于首过肝脏时被代谢,约26.00%的黄体酮被胃肠道代谢;静脉给药后黄体酮脂质体较对照组有更大的生物利用度,体内清除率降低。因此认为黄体酮制成脂质体后能有效促进黄体酮吸收,延长黄体酮在体内的驻留时间,提高黄体酮的生物利用度。
为了更有效地避免黄体酮在体内的代谢,进一步提高黄体酮的生物利用度。本文尝试对黄体酮脂质体用壳聚糖进行表面修饰,并测定了修饰脂质体的理化性质。结果脂质体经修饰后,包封率有所降低,脂质体荷正电,修饰脂质体在大鼠胃液中稳定性明显提高,生物利用度明显增加,初步证明本法形成的黄体酮脂质体表面修饰的可行性。
本文对黄体酮前体脂质体的体内外性质进行了一系列研究,对本法形成的脂质体的吸收机理、体内过程及首过效应进行了评价,为口服天然黄体酮前体脂质体制剂的进一步开发和应用奠定了基础。
As the female steroidal hormones,progesterone has been found to metabolize quickly and extensively after orally administrated,which leads to its poor and variable bioavailability,so progesterone is normally administrated by intramuscular route, however,local pain at the injection site is not insignificant and becomes an increasingly important issue as progesterone administration is prolonged.Liposome is one of the fastest growing drug delivery systems,for the delivery of sensitive molecules/compounds such as proteins and hormone,liposome could protect the incorporated agents from degradation,increase the absorption and bioavailability of drugs.In our article,a new kind of progesterone proliposome was made.After orally administrated or mixed with water,the liposome could be formed and the properties of progesterone liposome for improving absorption and protection against metabolism were determined.
At first,progesterone liposome was made by a new kind of proliposome method invented in our laboratories,and the prescription of liposome was optimized,and then the properties including morphology,particle size,protective effect in gastric and intestinal contents,acute toxicity,the absorption in vitro,the bioavailability in vivo and the first-pass effect were determined.There was not such report about progesterone liposome in china.
To optimize the prescription of progesterone proliposome,the single factor experiment and ternary phase diagram were used,and the ratio of drug and lecithin was determined. After proliposome was made,the acute toxicity was determined and the result demonstrated that progesterone liposome was safe with a low toxicity to mice and the LD50 was less than micronized progesterone soft capsule.The stability of liposome was observed through the stress testing and accelerated testing,the results showed that liposome was susceptive to temperature and light,so the liposome should be stored in shady and cool place.
During the determination of entrapment efficiency,High performance liquid chromatography was used to determine the contents of progesterone.The transmission electron microphotography and scanning electron microphotography was used to observe the morphology of progesterone liposome and blank liposome,the results showed the liposome was round with multilayer.The particle sizes and zeta potential of liposome were determined by using the nano-particle sizer,the results demonstrated that the average particle size of liposome was 103.7nm and zeta potential was -88.9mv.The gel filtration chromatography method was established to determine the entrapment efficiency of liposome,and then the influencing factors of entrapment efficiency were studied.The results showed that the entrapment efficiency of liposome was 54.95±9.98%and the ratio of drug and lecithin,diluted times might take an effect on the entrapment efficiency.The leakage rate of liposome at room temperature and 4~C were also studied through the determination of entrapment efficiency,and a low leakage rate in 4℃was observed. Furthermore,progesterone liposome was compared with progesterone liposome made by film evaporation method.The results indicated that the morphology of two kinds of liposome was same,but the entrapment efficiency of liposome made by our method was higher than the other,and the particle size of the former was lower than the latter,which the liposome made by our method was better than that made by film evaporation method. All the results indicated that progesterone liposome could be formed with our method.
To study the protective of liposome against degradation,a method in vitro was established and the residual contents of progesterone liposome versus time after mixed respectively with the artificial gastric juice,artificial intestinal juice or the grastric and intestinal contents of rats were determined.The results indicated that liposome could protect effectively progesterone against the trypsin when it was mixed with the duodenum and colon contents of rats.However,the results were not obvious when liposome was mixed with the other contents as above,because the conditions of intestinal contents was more like the true conditions than the artificial intestinal juice,it could be believed that the liposome could protect effectively progesterone against degradation at intestinal contents when taken orally.
A good absorption model in vitro,Caco-2 cell model,was established in our laboratory, and then the transport of liposome was determined after Caco-2 cell grew for up to twenty-one days and TEER was above 300Ω·cm~2.The results indicated progesterone belonged toⅡtype of drugs in BCS and its transport was active transport.The P_(app) at basolateral to apical direction was higher than that at apical to basolateral direction,and the P-gp inhibitor could improve the accumulative transport flux,which indicated there was P-glycoprotein at basolateral to apical direction.P-glycoprotein could act as a "drug pump" which could pump the drug out of the cells when the drug was absorped.On the other hand,progesterone liposome could improve the drug absorption through facilitating the transcellular transport and opening of tight junction to allow the paracellular pathway. Lastly,the cell toxicity of progesterone and progesterone liposome was determined through MTT experiments,the results showed that progesterone liposome had a little cell toxicity when diluted into 250 times with water.
The pharmacokinetics of progesterone liposome in rats removed ovaries was studied and compared with micronized progesterone soft capsule,and the relative bioavailability was calculated.The radioimmunoassay was used to determine the drug contents during the experiment.Furthermore,cross-over design was used in order to avoid the individual difference.The results indicated that the plasma concentration-time curves for progesterone liposome and micronized progesterone soft capsule fit two compartment open model after intragastric administration to the rats,there was significant difference in AUC between liposome and micronized progesterone,which suggested that liposome had higher bioavailability than micronized progesterone,the relative bioavailability is 289.19%.
It was also studied about the first-pass effect in rats of liposome through three administration route:intragastric administration,caudal injection and hepatic portal injection.The results demonstrated that in liposome group there were 49.49%drugs metabolized by liver and 26.00%drugs of total drugs metabolized by gastric and intestine. When administrated through the caudal injection,the bioavailability of liposome is higher than micronized progesterone soft capsule and the clearance of the former is less than the latter.All those results indicated progesterone liposome could improve the bioavailability of progesterone through improving the absorption and protecting progesterone against metabolism.
Moreover,in order to protect ulteriorly against metabolism in vivo and improve ulteriorly the bioavailability,liposome was tried to modify with chitosan,and the properties of chitosan modified liposome was determined and compared with liposome. The results indicated that the entrapment efficiency of chitosan modified liposome was lower than the liposome,the zeta potential of chitosan modified liposome was positive. All that results indicated that the chitosan modified liposome had been formed.
In our article,the feasibility of progesterone liposome was evaluated through the determination of liposome properties,and the absorption mechanism,the pharmaco- kinetics in vivo,and then the first-pass effect was studied.The results would lay a foundation for the development of progesterone proliposome.
引文
[1]贺云霞,程刚,孙进等.提高口服药物生物利用度制剂方法的研究进展[J].中国药剂学杂志.2003,1(4):165-171
[2]陈庆华,瞿文.多肽蛋白质药物的缓释剂型的研究进展[J].中国药学杂志.2000,35(3):147-150
[3]崔福德主编.《药剂学》(第五版)[M].人民卫生出版社.
[4]徐辉碧主编.《纳米医药》[M].清华大学出版社.
[5]仵文英,薛红安,邹晶等.脂质体制剂的靶向性特点及应用[J].中国中医药杂志.2004,2(5):253-254
[6]马宏达,郭涛.脂质体靶向载药系统的研究进展[J].中国药房.2004,15(11):697-698
[7]Payne NI,Browning I,Hynes CA.Characterization of proliposome[J].J Pharm Sci,1986,75(4):330
[8]王健,李明轩.前体脂质体的研究进展[J].中国医药工业杂志,2005,36(11):707-711
[9]Lorraine A.Fitzpatrick,M.D.,Andrew Good,M.D.Micronized progesterone:Clinical indications and comparison with current treatments[J].Fertility and sterility.1999,72(3):389-397
[10]Mare J.N.C.Keirse,MD,Dphil,DPH etc.Progesterone and preterm:Seventy years of"Deja Vu"or"Still To Be Seen"?[J].Birth.2004,31(3):230-235
[11]QUAN LJ,ZHAI ZC.The clinical practical application of the progesterone(in Chinese)[J].2001,20(2):101-102
[12]William E.Gibbons,M.D.,James R Toner,M.D.etc.Esperience with a novel vaginal progesterone preparation in a donor oocyte program[J].Fertility and sterility.1998,69(1):96-101
[13]Marc Germond,M.D.,Pada Capelli,M.D.,Giuliana Bruno,M.D.etc.Comparison of the efficacy and safety of two formulations of micronized progesterone(Ellios~(TM)and Utrogestan~(TM)) used as luteal phase support after in vitro fertilization[J].Fertility and sterility.2002,77(2):313-317
[14]Dominique de Ziegler,Renato Fanchin.Progesterone and progestins:applications in gynecology[J].Steroids.2000,65:671-679
[15]Brunode lignieres,M.D.Oral Micronized Progesterone.Clinical therapeutics[J].1999,21(1):41-60
[16]James A.Simon,M.D.,Mario L.Rocci,Jr.,Ph.D.,Denise E.Robinson,Ph.D.etc.The absorption of oral micronized progesterone:the effect of food,dose proportionality,and comprison with intramuslular progesterone[J].Fertility and sterility.1993,60(1):26-33
[17]C.Bourgain,P.Devroey,L.Van Waesberghe,J.Smitz.etc.Effects of natureal progesterone on the morphology of the endometrium in patients with primary ovarian failure[J].Human Reproduction.1990,5(5):537-543
[18]Wayne S.Maxson,M.D.,Joel T,Hargrove,M.D.Bioavailability of oral micronized progesterone[J].Fertility and sterility.1985,44(5):622-626
[19]Elsayed S.Arafat,Ph.D.,Joel T.Hargrove,M.D.,Wayne S,Maxson,M.D.etc.sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites[J].American Journal Obstetrics and Gynaecology.1988,159(5):1203-1209
[20]王琰,李正荣,潘正燕等.纳米脂质体包裹胰岛素经Caco-2细胞转运的研究[J].中国药理学通报.2005,21(1):78-81
[21]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报.2003,38(2):138-142
[22]山莽挺,王广基.Caco-2模型在肽类药物吸收特性研究中的应用[J].药学进展,2001,25(2):96-99
[23]高坤,孙进,何贵.Caco-2细胞模型在口服药物吸收研究中的应用[J].沈阳药科大学学报,2005,22(6):469-473
[24]胡景莲,张辉.脂质体制备方法研究进展[J].中国临床医药研究杂志.2004,113:11872-11874
[25]Goldbach P,Brochart H,Stamm A.Spray-Drying of liposomes for a pulmonary administration.Ⅱ.Retention of encapsulated materials[J].Drug Dev Ind Pharm,1993,19(19):2623-2636
[26]陈建明,张仰眉,高申.脂质体作为药物载体的研究进展[J].药学实践杂志.2001,19(4):214-218
[27]朱盛山.药物新剂型[M].化学工业出版社,2003:445
[28]RachelA.Miles,M.D.,Michae1F.Press,M.D.,Richard.J.Paulson,M.D.pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes:a comparative study[J].Fertility and sterility.1994,62(3):485-490
[29]Andrzej Slominski,celso E.Gomez-Sanchez,Mark F.Foecking.Metabolism of progesterone to DOC,corticosterone and 180HDOC in cultured human melanoma cells[J].FEBS Letters.1999,455:364-366
[30]Frank Z.stanczyk.All progestins are not created equal[J].Steroids.2003,68:879-890
[31]Elsayed S.Arafat,Ph.D.,Joel T.Hargrove,M.D.,Wayne S,Maxson,M.D.etc.sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites[J].American Journal Obstetrics and Gynaecology.1988,159(5):1203-t209
[32]Felicia V.Nowak.Distribution and metabolism of 20α-hydroxylated progestins in the female rat[J].Journal of steroid Biochemistry & Molecular Biology.2002,80:469-479
[33]吴正红,平其能,雷晓敏等.TMC包覆胰岛素脂质体的研究[J].中国药学杂志.2003,38(9):678-682
[34]魏树礼,张强.生物药剂学与药物动力学(第二版)[M].北京大学医学出版社,2004:408-410
[35]朱盛山.药物新剂型[M].化学工业出版社,2003:445
[36]全东琴,苏德森,顾学裘.药物载体空白脂质体前体的制备及性质的研究[J].沈阳药科大学学报.1999,16(3):160-163
[37]裴瑾,吕延成,杨翰仪.白细胞介素2(IL-2)脂质体的制备及包封率测定[J],白求恩医科大学学报.1996,22(3):319-320
[38]吴正红,平其能,宋赟梅.壳聚糖-EDTA轭合物对胰岛素口服纳米脂质体的影响[J].中国药科大学学报.2004,35(5):417-423
[39]Jean I.Pachot,Roger P.Botham.Experimental estimation of the role of P-glycoprotein in the pharmacokinetic behavior of telithromycin,a novel ketolide,in comparison with roxithromycin and other macrolides using the Caco-2 cell model[J].J Pharm Pharmaceut Sci.2003,6(1):1-12
[40]U.B.Ottoson,Umea,K.carlstrom,J.E.damber,etc.Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration[J].British Journal of Obstetrics and Gynaecology.1984,91:1111-1119
[41]Jiunn H.LIN,Masato Chiba,et al.Is the Role of the small Intestine in First-Pass Metabolism Overemphasized?[J].Pharmacological Reviews.1999,51(2):135-157
[42]梁文权主编.《生物药剂学与药物动力学》(第二版)[M].人民卫生出版社.2004:30
[43]Yamashita S,Furubayashi T,Kataoka M,et al.Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells[J].Eur J Pharm Sci.2000,10: 195-204.
[44]张志荣主编.《靶向治疗分子基础与靶向药物设计》t-M].科学出版社.2005:11
[45]Artursson P,Palm K,Luthman K.Caco-2 monolayers in experimental and theoretical predictions of drug transport[J].Adv Drug Deliv Rev.2001,46:27-43.
[46]杨海涛,王广基.Caco-2单层细胞模型及其在药学中的应用[J].药学学报.2000,35(10):797-800
[47]孙敏捷,盛星,胡一桥.Caco-2细胞单层模型的建立与验证[J].中国药学杂志.2006,41(18):1431-1434
[48]Arturson P,Karlsson J.Correlation between oral drag absorption in human and apparent drug permeability coefficients in human intestinal epithelial(Caco-2)cells[J].Biochem Biophys Res commun,1991,175(3):880
[49]Jiunn H.Lin,Masato Chiba,Effect of Dexamethasone on the Intestinal First-Pass Metabolism of Indinavir in Rats:Evidence of Cytochrome P-450 A and p-Glyco-protein Induction[J].Drug Metabolism and Disposition.1999,27(10):1187-1193
[50]Spalm TN,Weiner HL,Penaert PD,et al.Mesenteric lymph nodes are critical for the induction of high oral tolerance in the absence of peyer's potches[J].Eur J Immunol.2002,32(4)1109-1115
[51]Atsushi I,Hironmichi I,et al.Liposomalization of Lactoferrin Enhanced its Anti-inflammatory Effects via Oral Administration[J].Biol Pharm Bull.2005,28(9):1717-1721
[52]Frimori H,Miura S.Koseki S et al.Intravital observition of adlesion of lamina propria lymphoeytes to microvessels of small intestine in mice[J].Gastroenterology.2002,122(3):734-740
[53]K.Fotherby.Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy[J].Contracetion.1996,54:59-69
[54]K.C.KWAN.Oral bioavailability and first-pass effects[J].Drug Metabolism and Disposition.1997,25(12):1329-1336
[55]M.Herstermann,M.Agil,A.Buthe.etc.Metabolism and excretion of oestradiol-17βand progesterone in the Sumatran rhinoceros[J].Animal Reproduction Sciences.1998,53:159-172
[56]吴正红,平其能,宋斌梅等.壳聚糖及其EDTA轭合物双层包覆胰岛素脂质体的处方工艺优化[J].中国新药杂志.2004,13(9):805-809
[57]吴正红,平其能,宋斌梅等.壳聚糖和壳聚糖-EDTA接合物双层包覆胰岛素口服纳米脂质体的研究[J].药学学报.2004,39(11):933-938
[1] Lorraine A. Fitzpatrick, M. D., Andrew Good, M. D. Micronized progesterone: Clinical indications and comparison with current treatments[J]. Fertility and sterility. 1999;72(3):389-397
[2] Mare J. N. C. Keirse, MD, Dphil, DPH etc. Progesterone and preterm: Seventy years of "Deja Vu"or"Still To Be Seen"? [J] Birth. 2004;31(3):230-235
[3] QUAN LJ, ZHAI ZC. The clinical practical application of the progesterone (in Chinese) [J]. 2001, 20(2):101-102
[4] William E. Gibbons, M. D., James P. Toner, M. D. etc. Esperience with a novel vaginal progesterone preparation in a donor oocyte program[J]. Fertility and sterility. 1998;69(1):96-101
[5] Marc Germond, M. D., Pada Capelli, M. D., Giuliana Bruno, M. D. etc. Comparison of the efficacy and safety of two formulations of micronized progesterone(Ellios? and Utrogestan~(TM)) used as luteal phase support after in vitro fertilization[J]. Fertility and sterility. 2002;77(2):313-317
[6] Brunode lignieres, M. D. Oral Micronized Progesterone[J]. Clinical therapeutics. 1999;21(1):41-60
[7] James A. Simon, M. D., Mario L. Rocci, Jr., Ph. D., Denise E. Robinson, Ph. D. etc. The absorption of oral micronized progesterone:the effect of food, dose proportionality, and comprison with intramuslular progesterone[J]. Fertility and sterility. 1993;60(1):26-33
[8] K. Fotherby. Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy[J]. Contracetion. 1996;54:59-69
[9] Wayne S. Maxson, M. D., Joel T, Hargrove, M. D. Bioavailability of oral micronized progesterone[J]. Fertility and sterility. 1985;44(5):622-626
[10] Sven Johan Nillius, Elof D. B. Johansson. Plasma levels of progesterone after vaginal, rectal, or intramuscular administration of progesterone[J].American Journal of Obstetrics and Gynaecology. 1971; 110(4):470-477
[11]C. Bourgain, P. Devroey, L. Van Waesberghe, J. Smitz. etc. Effects of natureal progesterone on thh morphology of the endometrium in patients with primary ovarian failure[J]. Human Reproduction. 1990;5(5):537-543
[12] Peter O'Leary, Peter Feddema, Katherine Chan. Salivary but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre- and postmenopausal women[J]. Clinical Endocrinology. 2000;53:615-620
[13]RachelA. Miles, M. D., MichaelF. Press, M. D., Richard. J. Paulson, M. D. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study[J]. Fertility and sterility. 1994;62(3):485-490
[14]M. Herstermann, M. Agil, A. Buthe. etc. Metabolism and excretion of oestradiol-17β and progesterone in the Sumatran rhinoceros[J]. Animal Reproduction Sciences. 1998;53:159-172
[15]Kazuyoshi Ukena, Yoko Honda, Robert W. Lea. etc. Developmental changes in progesterone biosynthesis and metabolism in tbe quail brain[J]. Brain research. 2001;898:190-194
[16]Kristina M. Wasson, Stephen A. Watts. Progesterone metabolism in the ovaries and testes of the echinoid lytechiness variegates lamerck(Echinodermata) [J]. Comparative Biochemistry and physiology part C. 2000; 127:263-272
[17] Jie Zhang, Ling-Jie Ming, Jan SjOvall. etc. Progesterone metabolism in human fibroblasts is independent of P-glycoprotein levels and Niemann-Pick type C disease[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;70:123-131
[18]Merja A. Laine, Anita O. Ojanotko. Progesterone metabolism in human Saliva in vitro[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;70:109-113
[19]U. B. Ottoson, Umea, K. carlstrom, J. E. damber. etc. Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration[J]. British Journal of Obstetrics and Gynaecology. 1984;91:1111 -1119
[20]Andrzej Slominski, celso E. Gomez-Sanchez, Mark F. Foecking. Metabolism of progesterone to DOC, corticosterone and 180HDOC in cultured human melanoma cells[J]. FEBS Letters. 1999;455:364-366
[21] Frank Z. stanczyk. All progestins are not created equal[J]. Steroids. 2003;68:879-890
[22]Elsayed S. Arafat, Ph. D., Joel T. Hargrove, M. D., Wayne S, Maxson, M. D. etc. sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites [J]. American Journal Obstetrics and Gynaecology. 1988;159(5):1203-1209
[23] Felicia V. Nowak. Distribution and metabolism of 20a-hydroxylated progestins in the female rat[J]. Journal of steroid Biochemistry & Molecular Biology. 2002;80:469-479
[24]Monique Vincens, song-Yun Li, Georges Pelletier. Inhibitory effect of 5β-pregnan-3α-ol-one on gonadotropin-releasing hormone gene expression in the male rat[J]. European Journal of Pharmacology. 1994;260:157-162
[25]DARRELL. W. Brann, carlA. D. Putnam, virendra B. Mahesh. γ-Aminobutyric AcidA Receptors Mediate 3α-Hydroxy-5α-Pregnan-20-one-Induced Gonadotropin Secretion Endocrinology[J]. 1989; 126(4): 1854-1859
[26]Jung-Testes. A. Do Thi. H. Koenig, F. Desarnaud. Progesterone as a neurosteroid: synthesis and actions in rat glial cells[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;69:97-107
[27]Sonia Darison and susan R. Davis. Hormone replacement therapy:current controversies[J]. clinical Endocrinology. 2003;58:249-261
[28] Anthony P. Cheung. Acute effects of estradiol and progesterone on insulin, lipids and lipoproteins in postmenopausal women:a pilot study [J]. Maturitas. 2000;35:45-50
[29] B de Lignieres & S Silberstein. Pharmacodynamics of oestrogens and progestogens. Cephalalgia[J]. 2000;20:200-207
[30] Dominique de Ziegler, Renato Fanchin. Progesterone and progestins:applications in gynecology[J]. Steroids.2000;65:671-679
[31] William E. Gibbons, M. D., James P. Toner, M. D., Ph. D. etc. Experience with a novel vaginal progesterone preparation in a donor oocyte program[J]. Fertility and sterility. 1998;69(1):96-101
[32] Tally Lecy, Yael Yain, Itai Bar-Hava. Pharmacokinetics of the progesterone- containing vaginal tablet and its use in assisted reproduction[J]. Steroids. 2000;65:645-649
[33] S. R. Jameela, T. V. Kumary, A. V. Lal. etc. progesterone-loaded chitsan microspheres:a long acting biodegradable controlled delivery system[J]. Journal of controlled Release. 1998;52:17-24
[34]B. Bunter, M. Nouak, J. Kasperczyk. etc. The application of microspheres from the copolymers of lactide ands-caprolactone to the controlled release of steroids[J]. Journal of Controlled Release. 1998;56:159-167
[35] F. Courteille, J. P. Benoit and C. Thies. The morphology of progesterone-loaded polystyrene microspheres [J]. Journal of Controlled Release. 1994;31(1):17-26
[36] Isabella Orienti and Vittorio Zecchi. Progesterone-loaded albumin microparticles [J]. Journal of Controlled Release. 1993;27(1):1-7
[37]Yukio Aso, Sumie Yoshioka and Tadao Terao. Effects of storage on the physicochemical properties and release characteristics of progesterone-loaded poly(1-lactide)microspheres[J].International Journal of Pharmaceutics.1993;93(5):153-159
[38]Vinayak P.Sant,Daman Smith,Jean-Christophe Leroux.Novel pH-sensitive supramolicular assemblies for oral delivery of poorly water soluble drugs:preparation and characterization[J].Journal of Controlled Release.2004;97:310-312
[2]陈庆华,瞿文.多肽蛋白质药物的缓释剂型的研究进展[J].中国药学杂志.2000,35(3):147-150
[3]崔福德主编.《药剂学》(第五版)[M].人民卫生出版社.
[4]徐辉碧主编.《纳米医药》[M].清华大学出版社.
[5]仵文英,薛红安,邹晶等.脂质体制剂的靶向性特点及应用[J].中国中医药杂志.2004,2(5):253-254
[6]马宏达,郭涛.脂质体靶向载药系统的研究进展[J].中国药房.2004,15(11):697-698
[7]Payne NI,Browning I,Hynes CA.Characterization of proliposome[J].J Pharm Sci,1986,75(4):330
[8]王健,李明轩.前体脂质体的研究进展[J].中国医药工业杂志,2005,36(11):707-711
[9]Lorraine A.Fitzpatrick,M.D.,Andrew Good,M.D.Micronized progesterone:Clinical indications and comparison with current treatments[J].Fertility and sterility.1999,72(3):389-397
[10]Mare J.N.C.Keirse,MD,Dphil,DPH etc.Progesterone and preterm:Seventy years of"Deja Vu"or"Still To Be Seen"?[J].Birth.2004,31(3):230-235
[11]QUAN LJ,ZHAI ZC.The clinical practical application of the progesterone(in Chinese)[J].2001,20(2):101-102
[12]William E.Gibbons,M.D.,James R Toner,M.D.etc.Esperience with a novel vaginal progesterone preparation in a donor oocyte program[J].Fertility and sterility.1998,69(1):96-101
[13]Marc Germond,M.D.,Pada Capelli,M.D.,Giuliana Bruno,M.D.etc.Comparison of the efficacy and safety of two formulations of micronized progesterone(Ellios~(TM)and Utrogestan~(TM)) used as luteal phase support after in vitro fertilization[J].Fertility and sterility.2002,77(2):313-317
[14]Dominique de Ziegler,Renato Fanchin.Progesterone and progestins:applications in gynecology[J].Steroids.2000,65:671-679
[15]Brunode lignieres,M.D.Oral Micronized Progesterone.Clinical therapeutics[J].1999,21(1):41-60
[16]James A.Simon,M.D.,Mario L.Rocci,Jr.,Ph.D.,Denise E.Robinson,Ph.D.etc.The absorption of oral micronized progesterone:the effect of food,dose proportionality,and comprison with intramuslular progesterone[J].Fertility and sterility.1993,60(1):26-33
[17]C.Bourgain,P.Devroey,L.Van Waesberghe,J.Smitz.etc.Effects of natureal progesterone on the morphology of the endometrium in patients with primary ovarian failure[J].Human Reproduction.1990,5(5):537-543
[18]Wayne S.Maxson,M.D.,Joel T,Hargrove,M.D.Bioavailability of oral micronized progesterone[J].Fertility and sterility.1985,44(5):622-626
[19]Elsayed S.Arafat,Ph.D.,Joel T.Hargrove,M.D.,Wayne S,Maxson,M.D.etc.sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites[J].American Journal Obstetrics and Gynaecology.1988,159(5):1203-1209
[20]王琰,李正荣,潘正燕等.纳米脂质体包裹胰岛素经Caco-2细胞转运的研究[J].中国药理学通报.2005,21(1):78-81
[21]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报.2003,38(2):138-142
[22]山莽挺,王广基.Caco-2模型在肽类药物吸收特性研究中的应用[J].药学进展,2001,25(2):96-99
[23]高坤,孙进,何贵.Caco-2细胞模型在口服药物吸收研究中的应用[J].沈阳药科大学学报,2005,22(6):469-473
[24]胡景莲,张辉.脂质体制备方法研究进展[J].中国临床医药研究杂志.2004,113:11872-11874
[25]Goldbach P,Brochart H,Stamm A.Spray-Drying of liposomes for a pulmonary administration.Ⅱ.Retention of encapsulated materials[J].Drug Dev Ind Pharm,1993,19(19):2623-2636
[26]陈建明,张仰眉,高申.脂质体作为药物载体的研究进展[J].药学实践杂志.2001,19(4):214-218
[27]朱盛山.药物新剂型[M].化学工业出版社,2003:445
[28]RachelA.Miles,M.D.,Michae1F.Press,M.D.,Richard.J.Paulson,M.D.pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes:a comparative study[J].Fertility and sterility.1994,62(3):485-490
[29]Andrzej Slominski,celso E.Gomez-Sanchez,Mark F.Foecking.Metabolism of progesterone to DOC,corticosterone and 180HDOC in cultured human melanoma cells[J].FEBS Letters.1999,455:364-366
[30]Frank Z.stanczyk.All progestins are not created equal[J].Steroids.2003,68:879-890
[31]Elsayed S.Arafat,Ph.D.,Joel T.Hargrove,M.D.,Wayne S,Maxson,M.D.etc.sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites[J].American Journal Obstetrics and Gynaecology.1988,159(5):1203-t209
[32]Felicia V.Nowak.Distribution and metabolism of 20α-hydroxylated progestins in the female rat[J].Journal of steroid Biochemistry & Molecular Biology.2002,80:469-479
[33]吴正红,平其能,雷晓敏等.TMC包覆胰岛素脂质体的研究[J].中国药学杂志.2003,38(9):678-682
[34]魏树礼,张强.生物药剂学与药物动力学(第二版)[M].北京大学医学出版社,2004:408-410
[35]朱盛山.药物新剂型[M].化学工业出版社,2003:445
[36]全东琴,苏德森,顾学裘.药物载体空白脂质体前体的制备及性质的研究[J].沈阳药科大学学报.1999,16(3):160-163
[37]裴瑾,吕延成,杨翰仪.白细胞介素2(IL-2)脂质体的制备及包封率测定[J],白求恩医科大学学报.1996,22(3):319-320
[38]吴正红,平其能,宋赟梅.壳聚糖-EDTA轭合物对胰岛素口服纳米脂质体的影响[J].中国药科大学学报.2004,35(5):417-423
[39]Jean I.Pachot,Roger P.Botham.Experimental estimation of the role of P-glycoprotein in the pharmacokinetic behavior of telithromycin,a novel ketolide,in comparison with roxithromycin and other macrolides using the Caco-2 cell model[J].J Pharm Pharmaceut Sci.2003,6(1):1-12
[40]U.B.Ottoson,Umea,K.carlstrom,J.E.damber,etc.Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration[J].British Journal of Obstetrics and Gynaecology.1984,91:1111-1119
[41]Jiunn H.LIN,Masato Chiba,et al.Is the Role of the small Intestine in First-Pass Metabolism Overemphasized?[J].Pharmacological Reviews.1999,51(2):135-157
[42]梁文权主编.《生物药剂学与药物动力学》(第二版)[M].人民卫生出版社.2004:30
[43]Yamashita S,Furubayashi T,Kataoka M,et al.Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells[J].Eur J Pharm Sci.2000,10: 195-204.
[44]张志荣主编.《靶向治疗分子基础与靶向药物设计》t-M].科学出版社.2005:11
[45]Artursson P,Palm K,Luthman K.Caco-2 monolayers in experimental and theoretical predictions of drug transport[J].Adv Drug Deliv Rev.2001,46:27-43.
[46]杨海涛,王广基.Caco-2单层细胞模型及其在药学中的应用[J].药学学报.2000,35(10):797-800
[47]孙敏捷,盛星,胡一桥.Caco-2细胞单层模型的建立与验证[J].中国药学杂志.2006,41(18):1431-1434
[48]Arturson P,Karlsson J.Correlation between oral drag absorption in human and apparent drug permeability coefficients in human intestinal epithelial(Caco-2)cells[J].Biochem Biophys Res commun,1991,175(3):880
[49]Jiunn H.Lin,Masato Chiba,Effect of Dexamethasone on the Intestinal First-Pass Metabolism of Indinavir in Rats:Evidence of Cytochrome P-450 A and p-Glyco-protein Induction[J].Drug Metabolism and Disposition.1999,27(10):1187-1193
[50]Spalm TN,Weiner HL,Penaert PD,et al.Mesenteric lymph nodes are critical for the induction of high oral tolerance in the absence of peyer's potches[J].Eur J Immunol.2002,32(4)1109-1115
[51]Atsushi I,Hironmichi I,et al.Liposomalization of Lactoferrin Enhanced its Anti-inflammatory Effects via Oral Administration[J].Biol Pharm Bull.2005,28(9):1717-1721
[52]Frimori H,Miura S.Koseki S et al.Intravital observition of adlesion of lamina propria lymphoeytes to microvessels of small intestine in mice[J].Gastroenterology.2002,122(3):734-740
[53]K.Fotherby.Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy[J].Contracetion.1996,54:59-69
[54]K.C.KWAN.Oral bioavailability and first-pass effects[J].Drug Metabolism and Disposition.1997,25(12):1329-1336
[55]M.Herstermann,M.Agil,A.Buthe.etc.Metabolism and excretion of oestradiol-17βand progesterone in the Sumatran rhinoceros[J].Animal Reproduction Sciences.1998,53:159-172
[56]吴正红,平其能,宋斌梅等.壳聚糖及其EDTA轭合物双层包覆胰岛素脂质体的处方工艺优化[J].中国新药杂志.2004,13(9):805-809
[57]吴正红,平其能,宋斌梅等.壳聚糖和壳聚糖-EDTA接合物双层包覆胰岛素口服纳米脂质体的研究[J].药学学报.2004,39(11):933-938
[1] Lorraine A. Fitzpatrick, M. D., Andrew Good, M. D. Micronized progesterone: Clinical indications and comparison with current treatments[J]. Fertility and sterility. 1999;72(3):389-397
[2] Mare J. N. C. Keirse, MD, Dphil, DPH etc. Progesterone and preterm: Seventy years of "Deja Vu"or"Still To Be Seen"? [J] Birth. 2004;31(3):230-235
[3] QUAN LJ, ZHAI ZC. The clinical practical application of the progesterone (in Chinese) [J]. 2001, 20(2):101-102
[4] William E. Gibbons, M. D., James P. Toner, M. D. etc. Esperience with a novel vaginal progesterone preparation in a donor oocyte program[J]. Fertility and sterility. 1998;69(1):96-101
[5] Marc Germond, M. D., Pada Capelli, M. D., Giuliana Bruno, M. D. etc. Comparison of the efficacy and safety of two formulations of micronized progesterone(Ellios? and Utrogestan~(TM)) used as luteal phase support after in vitro fertilization[J]. Fertility and sterility. 2002;77(2):313-317
[6] Brunode lignieres, M. D. Oral Micronized Progesterone[J]. Clinical therapeutics. 1999;21(1):41-60
[7] James A. Simon, M. D., Mario L. Rocci, Jr., Ph. D., Denise E. Robinson, Ph. D. etc. The absorption of oral micronized progesterone:the effect of food, dose proportionality, and comprison with intramuslular progesterone[J]. Fertility and sterility. 1993;60(1):26-33
[8] K. Fotherby. Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy[J]. Contracetion. 1996;54:59-69
[9] Wayne S. Maxson, M. D., Joel T, Hargrove, M. D. Bioavailability of oral micronized progesterone[J]. Fertility and sterility. 1985;44(5):622-626
[10] Sven Johan Nillius, Elof D. B. Johansson. Plasma levels of progesterone after vaginal, rectal, or intramuscular administration of progesterone[J].American Journal of Obstetrics and Gynaecology. 1971; 110(4):470-477
[11]C. Bourgain, P. Devroey, L. Van Waesberghe, J. Smitz. etc. Effects of natureal progesterone on thh morphology of the endometrium in patients with primary ovarian failure[J]. Human Reproduction. 1990;5(5):537-543
[12] Peter O'Leary, Peter Feddema, Katherine Chan. Salivary but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre- and postmenopausal women[J]. Clinical Endocrinology. 2000;53:615-620
[13]RachelA. Miles, M. D., MichaelF. Press, M. D., Richard. J. Paulson, M. D. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study[J]. Fertility and sterility. 1994;62(3):485-490
[14]M. Herstermann, M. Agil, A. Buthe. etc. Metabolism and excretion of oestradiol-17β and progesterone in the Sumatran rhinoceros[J]. Animal Reproduction Sciences. 1998;53:159-172
[15]Kazuyoshi Ukena, Yoko Honda, Robert W. Lea. etc. Developmental changes in progesterone biosynthesis and metabolism in tbe quail brain[J]. Brain research. 2001;898:190-194
[16]Kristina M. Wasson, Stephen A. Watts. Progesterone metabolism in the ovaries and testes of the echinoid lytechiness variegates lamerck(Echinodermata) [J]. Comparative Biochemistry and physiology part C. 2000; 127:263-272
[17] Jie Zhang, Ling-Jie Ming, Jan SjOvall. etc. Progesterone metabolism in human fibroblasts is independent of P-glycoprotein levels and Niemann-Pick type C disease[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;70:123-131
[18]Merja A. Laine, Anita O. Ojanotko. Progesterone metabolism in human Saliva in vitro[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;70:109-113
[19]U. B. Ottoson, Umea, K. carlstrom, J. E. damber. etc. Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration[J]. British Journal of Obstetrics and Gynaecology. 1984;91:1111 -1119
[20]Andrzej Slominski, celso E. Gomez-Sanchez, Mark F. Foecking. Metabolism of progesterone to DOC, corticosterone and 180HDOC in cultured human melanoma cells[J]. FEBS Letters. 1999;455:364-366
[21] Frank Z. stanczyk. All progestins are not created equal[J]. Steroids. 2003;68:879-890
[22]Elsayed S. Arafat, Ph. D., Joel T. Hargrove, M. D., Wayne S, Maxson, M. D. etc. sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites [J]. American Journal Obstetrics and Gynaecology. 1988;159(5):1203-1209
[23] Felicia V. Nowak. Distribution and metabolism of 20a-hydroxylated progestins in the female rat[J]. Journal of steroid Biochemistry & Molecular Biology. 2002;80:469-479
[24]Monique Vincens, song-Yun Li, Georges Pelletier. Inhibitory effect of 5β-pregnan-3α-ol-one on gonadotropin-releasing hormone gene expression in the male rat[J]. European Journal of Pharmacology. 1994;260:157-162
[25]DARRELL. W. Brann, carlA. D. Putnam, virendra B. Mahesh. γ-Aminobutyric AcidA Receptors Mediate 3α-Hydroxy-5α-Pregnan-20-one-Induced Gonadotropin Secretion Endocrinology[J]. 1989; 126(4): 1854-1859
[26]Jung-Testes. A. Do Thi. H. Koenig, F. Desarnaud. Progesterone as a neurosteroid: synthesis and actions in rat glial cells[J]. Journal of steroid Biochemistry and Molecular Biology. 1999;69:97-107
[27]Sonia Darison and susan R. Davis. Hormone replacement therapy:current controversies[J]. clinical Endocrinology. 2003;58:249-261
[28] Anthony P. Cheung. Acute effects of estradiol and progesterone on insulin, lipids and lipoproteins in postmenopausal women:a pilot study [J]. Maturitas. 2000;35:45-50
[29] B de Lignieres & S Silberstein. Pharmacodynamics of oestrogens and progestogens. Cephalalgia[J]. 2000;20:200-207
[30] Dominique de Ziegler, Renato Fanchin. Progesterone and progestins:applications in gynecology[J]. Steroids.2000;65:671-679
[31] William E. Gibbons, M. D., James P. Toner, M. D., Ph. D. etc. Experience with a novel vaginal progesterone preparation in a donor oocyte program[J]. Fertility and sterility. 1998;69(1):96-101
[32] Tally Lecy, Yael Yain, Itai Bar-Hava. Pharmacokinetics of the progesterone- containing vaginal tablet and its use in assisted reproduction[J]. Steroids. 2000;65:645-649
[33] S. R. Jameela, T. V. Kumary, A. V. Lal. etc. progesterone-loaded chitsan microspheres:a long acting biodegradable controlled delivery system[J]. Journal of controlled Release. 1998;52:17-24
[34]B. Bunter, M. Nouak, J. Kasperczyk. etc. The application of microspheres from the copolymers of lactide ands-caprolactone to the controlled release of steroids[J]. Journal of Controlled Release. 1998;56:159-167
[35] F. Courteille, J. P. Benoit and C. Thies. The morphology of progesterone-loaded polystyrene microspheres [J]. Journal of Controlled Release. 1994;31(1):17-26
[36] Isabella Orienti and Vittorio Zecchi. Progesterone-loaded albumin microparticles [J]. Journal of Controlled Release. 1993;27(1):1-7
[37]Yukio Aso, Sumie Yoshioka and Tadao Terao. Effects of storage on the physicochemical properties and release characteristics of progesterone-loaded poly(1-lactide)microspheres[J].International Journal of Pharmaceutics.1993;93(5):153-159
[38]Vinayak P.Sant,Daman Smith,Jean-Christophe Leroux.Novel pH-sensitive supramolicular assemblies for oral delivery of poorly water soluble drugs:preparation and characterization[J].Journal of Controlled Release.2004;97:310-312