前列腺素E1透皮给药制剂的研究
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摘要
前列腺素E1(PGE1，prostaglaJldin E1) 又名前列地尔(alprostadil)，是人体
内重要的生理活性物质，具有舒张血管平滑肌，扩张外周血管和冠状血管，抑制
血小板聚集，改善末梢循环，调节炎症细胞活性等多种生理药理作用。该药临床
上广泛用于治疗严重的外周血管疾病、男性性功能障碍(ED)、脑动脉高压症、
缺血性心脏病、高血脂，可辅助治疗肝炎、糖尿病、消化性溃疡、急慢性肾衰、
胰腺炎等疾病。具有剂量小、疗效显著、毒副作用小的特点。但该药理化性质不
稳定，水溶性差，胃肠道降解严重，口服无效，这给制剂学研究带来一定困难。
目前国内外上市的前列腺素E1剂型有冰干粉针剂、注射乳剂，外用制剂有乳膏、
凝胶剂和尿道栓。其中注射剂存在明显的血管刺激性，给患者带来一定痛苦。国
内外用制剂有乳膏剂和尿道栓，均用于ED的治疗。
本研究采用现代药剂学新技术，选择了最佳溶媒系统，不仅成功地解决了前
列腺素E1的化学稳定性和溶解性等问题。而且筛选出对其透皮吸收相当有效的促
渗剂，6小时的累积渗透量Q比基础处方提高5． 01倍，渗透系数Kp提高5． 2
倍。又通过系统评价确定了处方和工艺。从而开展了如下研究，证明前列腺素E1
透皮制剂是安全、有效、质量可控的前列腺素E1新剂型。
建立了稳定性分析方法-HPLC法，系统研究了前列腺素E1透皮给药制剂的
稳定性，包括因素试验、加速试验和长期试验，证明本剂型稳定性良好。
军笋医学群学脂颐士学夕活戈)
威丹罗清El透贫给药脚脚时研男价丈卿要心
在对家兔皮肤刺激性试验和豚鼠皮肤变态反应试验中，没有产生可逆性炎性
症状和免疫传递的皮肤反应。证明前列腺素E;透皮制剂不具刺激性和致敏性，生
物相容性好，适合人体长期使用。
由于前列腺素El给药剂量极微(100林留次)，体内代谢极快，tl/2为0.5一
4min，血浆蛋白结合率约为93%，其中81%与白蛋白结合，故体内检测方法的灵
敏度限制了该药药代动力学研究。本研究以建立的在体兔耳静脉灌流方法，研究
了前列腺素E，透皮制剂于在体皮肤的透过性，佐证了该制剂皮肤透过性良好。
本研究的处方独特，不仅成功解决稳定性和溶解度的问题，而且透皮吸收
快，生物利用度高，对皮肤无刺激性和致敏性，使用方便，为其开发新剂型打下
良好基础。该剂型国内外无文献报道，拟申报国家发明专利。
Prostaglandin Ei(PGEi), also named alprostadil, is an important naturally occurring biological active substance of human body. There are many physiological and pharmacological functions of PGEi such as relaxing vascular smooth muscles, inducing vasodilatation of coronary artery and periphery vessels, inhibiting platelet agglutination, improving peripheral circulation and adjusting activity of inflammation cells etc. It is used clinically to treat periphery vessel disease, erection dysfunction(ED), cerebral artery hypertension, ischemic heart disease and hyperlipidemia. It is also used as assistant therapy method in treating hepatitis, diabetes, peptic ulcer, renal failure and pancreatitis. PGEi has the characteristic of low dosage, remarkable curative effects and fewer side effects. But the unstable physicochemical properties, poor solubility in water, severe degradation in gastrointestinal tract and ineffectiveness take orally which made the pharmacy research more difficult. Now the dosage forms in market a
re dry powder, emulsion for injection and cream, jellies, urethral suppository for external use. The injection preparations often induce obvious vascular irritation, which bring patients pains. The external dosage forms in domestic market are cream and urethral suppository. Both of them are used in therapy of erection dysfunction(ED).
The research found the optimal menstrua system by modern pharmacy technologies. The system successfully solved the problems of chemical stability and solubility of PGEi. The screening penetration test in vitro help us to find the most active enhancer, which cause 5.01-fold cumulative amount and 5.2-fold Kp increase contrast to basic formulation. At last, the formulation was determined through systematic evaluation. The following studies proved that the PGEi transdermal delivery system was safe, effective and quality- controllable.
A stability study method of PGEi was developed. The stability study on transdermal delivery system including factors test, accelerating test and long-term test
indicated that the dosage form was stable, nearly without any changes during the stability study.
In the studies of irritation on rabbit skins and allergic response on Guinea pig skins showed neither reversible inflammations nor immune passing reaction. They proved that the form wouldn't induce irritation and sensitization. It was well biological consistent and able to use in long-term.
Because of the minim administration dose (100fig per time), the fast metabolize course (ti/2was 0.54 min), the high plasma protein binding rate (nearly 93%) and the sensitivity of determination constrained the feasibility of pharmacokinetics study in vivo. So we established in situ perfused rabbit ear model for percutaneous absorption to evaluate the penetration abilily of PGEi transdermal delivery system on live skins. The results showed the forms had good permeation.
The particular formulation of PGEi transdermal delivery system not only solved the solved the problems of chemical stability and solubility, but also showed high penetration rate and bioavailability. It was safe and convenient. The study provide a theory basis for developing new dosage form of PGEi in future. The PGEi transdermal delivery system had been reported previously. The application of China Patents will be performed.
内重要的生理活性物质，具有舒张血管平滑肌，扩张外周血管和冠状血管，抑制
血小板聚集，改善末梢循环，调节炎症细胞活性等多种生理药理作用。该药临床
上广泛用于治疗严重的外周血管疾病、男性性功能障碍(ED)、脑动脉高压症、
缺血性心脏病、高血脂，可辅助治疗肝炎、糖尿病、消化性溃疡、急慢性肾衰、
胰腺炎等疾病。具有剂量小、疗效显著、毒副作用小的特点。但该药理化性质不
稳定，水溶性差，胃肠道降解严重，口服无效，这给制剂学研究带来一定困难。
目前国内外上市的前列腺素E1剂型有冰干粉针剂、注射乳剂，外用制剂有乳膏、
凝胶剂和尿道栓。其中注射剂存在明显的血管刺激性，给患者带来一定痛苦。国
内外用制剂有乳膏剂和尿道栓，均用于ED的治疗。
本研究采用现代药剂学新技术，选择了最佳溶媒系统，不仅成功地解决了前
列腺素E1的化学稳定性和溶解性等问题。而且筛选出对其透皮吸收相当有效的促
渗剂，6小时的累积渗透量Q比基础处方提高5． 01倍，渗透系数Kp提高5． 2
倍。又通过系统评价确定了处方和工艺。从而开展了如下研究，证明前列腺素E1
透皮制剂是安全、有效、质量可控的前列腺素E1新剂型。
建立了稳定性分析方法-HPLC法，系统研究了前列腺素E1透皮给药制剂的
稳定性，包括因素试验、加速试验和长期试验，证明本剂型稳定性良好。
军笋医学群学脂颐士学夕活戈)
威丹罗清El透贫给药脚脚时研男价丈卿要心
在对家兔皮肤刺激性试验和豚鼠皮肤变态反应试验中，没有产生可逆性炎性
症状和免疫传递的皮肤反应。证明前列腺素E;透皮制剂不具刺激性和致敏性，生
物相容性好，适合人体长期使用。
由于前列腺素El给药剂量极微(100林留次)，体内代谢极快，tl/2为0.5一
4min，血浆蛋白结合率约为93%，其中81%与白蛋白结合，故体内检测方法的灵
敏度限制了该药药代动力学研究。本研究以建立的在体兔耳静脉灌流方法，研究
了前列腺素E，透皮制剂于在体皮肤的透过性，佐证了该制剂皮肤透过性良好。
本研究的处方独特，不仅成功解决稳定性和溶解度的问题，而且透皮吸收
快，生物利用度高，对皮肤无刺激性和致敏性，使用方便，为其开发新剂型打下
良好基础。该剂型国内外无文献报道，拟申报国家发明专利。
Prostaglandin Ei(PGEi), also named alprostadil, is an important naturally occurring biological active substance of human body. There are many physiological and pharmacological functions of PGEi such as relaxing vascular smooth muscles, inducing vasodilatation of coronary artery and periphery vessels, inhibiting platelet agglutination, improving peripheral circulation and adjusting activity of inflammation cells etc. It is used clinically to treat periphery vessel disease, erection dysfunction(ED), cerebral artery hypertension, ischemic heart disease and hyperlipidemia. It is also used as assistant therapy method in treating hepatitis, diabetes, peptic ulcer, renal failure and pancreatitis. PGEi has the characteristic of low dosage, remarkable curative effects and fewer side effects. But the unstable physicochemical properties, poor solubility in water, severe degradation in gastrointestinal tract and ineffectiveness take orally which made the pharmacy research more difficult. Now the dosage forms in market a
re dry powder, emulsion for injection and cream, jellies, urethral suppository for external use. The injection preparations often induce obvious vascular irritation, which bring patients pains. The external dosage forms in domestic market are cream and urethral suppository. Both of them are used in therapy of erection dysfunction(ED).
The research found the optimal menstrua system by modern pharmacy technologies. The system successfully solved the problems of chemical stability and solubility of PGEi. The screening penetration test in vitro help us to find the most active enhancer, which cause 5.01-fold cumulative amount and 5.2-fold Kp increase contrast to basic formulation. At last, the formulation was determined through systematic evaluation. The following studies proved that the PGEi transdermal delivery system was safe, effective and quality- controllable.
A stability study method of PGEi was developed. The stability study on transdermal delivery system including factors test, accelerating test and long-term test
indicated that the dosage form was stable, nearly without any changes during the stability study.
In the studies of irritation on rabbit skins and allergic response on Guinea pig skins showed neither reversible inflammations nor immune passing reaction. They proved that the form wouldn't induce irritation and sensitization. It was well biological consistent and able to use in long-term.
Because of the minim administration dose (100fig per time), the fast metabolize course (ti/2was 0.54 min), the high plasma protein binding rate (nearly 93%) and the sensitivity of determination constrained the feasibility of pharmacokinetics study in vivo. So we established in situ perfused rabbit ear model for percutaneous absorption to evaluate the penetration abilily of PGEi transdermal delivery system on live skins. The results showed the forms had good permeation.
The particular formulation of PGEi transdermal delivery system not only solved the solved the problems of chemical stability and solubility, but also showed high penetration rate and bioavailability. It was safe and convenient. The study provide a theory basis for developing new dosage form of PGEi in future. The PGEi transdermal delivery system had been reported previously. The application of China Patents will be performed.
引文
[1] 郑俊民主编．经皮给药新剂型．人民卫生出版社．
[2] 梁秉文主编．经皮给药制剂．中国医药科技出版社．
[3] 陆彬主编．药物新剂型与新技术．人民卫生出版社．
[4] Scheider WP,Axen U,Lincoln FH,et al.The synthesis of prostaglandin E1 and related substances.Journal of American Chemistry Society,1969,91:5732．
[5] Nelson CA,Seamon KB.Binding of [3H]forskolin to human platelet membranes.Regulation by guanyl-5-ylimdodiphosphate,NaF,and prostaglandin E1 and D2． Journal of Biological chemistry.1986,261:13469．
[6] 邱丽等，前列腺素E1的临床应用．中国临床药学杂志．2001，10(1) ：48-51．
[7] 马云玲等，前列腺素E1在急诊临床中的应用进展．医药综述2001，7(9) ：571-572．
[8] 田庆印等，前列腺素E1在心血管疾病中的临床应用．药学进展2000，24(2) ：93-97
[9] Noda kanji.PGE1-containing pharmaceutical for external use.JP,1991,3083925,1991-4-9．
[10] Sekiyama Taiji.Prostaglandin E1-containing fat emulsion-loaded aerosol.JP,1992,4300833,1992-10-23．
[11] Hirotoshi Adachi,Tetsumi Me,Fumitoshi Hirayama,et al.Stabilization of prostaglandin E1 in fatty alcohol propylene glycol ointment by acid cyclodextrin derivative,O-carboxymethyl-O-ethyl-β-cyclodextrin.Chem.Pharm.Bull,1992,40(6) :1586-1591
[12] 罗明生，高天惠．药剂辅料大全．四川科学技术出版社．1993． 3．
[13] 陈妍等，国产静注前列腺素E1(PGE1) 质量研究．中国临床药理学杂质
[14] Ming-Thau Sheu,Investigation of the percutaneous penetration of prostaglandin E1 and its alkyl ester.Journal of Controlled Release 55(1998) 153~160．
[15] 中国药典2000年版二部 附录XIXC药物稳定性指导原则附录197-附录200．
[16] Horst Schweer,Jochen Kammer,et,simultaneous determination of prostanoids in plasma by gas chromatography-negative-ion chemical-ionization mass spectrometry,journal of chromatography,338(1985) :273-280．
[17] W.H.HESSE,H.SCHWEER,H.W.SEYBERTH.separation and determination of prostaglandin E1 metabolites by high-performance liquid chromatography.Journal of chromatography.533(1990) :159-165．
[2] 梁秉文主编．经皮给药制剂．中国医药科技出版社．
[3] 陆彬主编．药物新剂型与新技术．人民卫生出版社．
[4] Scheider WP,Axen U,Lincoln FH,et al.The synthesis of prostaglandin E1 and related substances.Journal of American Chemistry Society,1969,91:5732．
[5] Nelson CA,Seamon KB.Binding of [3H]forskolin to human platelet membranes.Regulation by guanyl-5-ylimdodiphosphate,NaF,and prostaglandin E1 and D2． Journal of Biological chemistry.1986,261:13469．
[6] 邱丽等，前列腺素E1的临床应用．中国临床药学杂志．2001，10(1) ：48-51．
[7] 马云玲等，前列腺素E1在急诊临床中的应用进展．医药综述2001，7(9) ：571-572．
[8] 田庆印等，前列腺素E1在心血管疾病中的临床应用．药学进展2000，24(2) ：93-97
[9] Noda kanji.PGE1-containing pharmaceutical for external use.JP,1991,3083925,1991-4-9．
[10] Sekiyama Taiji.Prostaglandin E1-containing fat emulsion-loaded aerosol.JP,1992,4300833,1992-10-23．
[11] Hirotoshi Adachi,Tetsumi Me,Fumitoshi Hirayama,et al.Stabilization of prostaglandin E1 in fatty alcohol propylene glycol ointment by acid cyclodextrin derivative,O-carboxymethyl-O-ethyl-β-cyclodextrin.Chem.Pharm.Bull,1992,40(6) :1586-1591
[12] 罗明生，高天惠．药剂辅料大全．四川科学技术出版社．1993． 3．
[13] 陈妍等，国产静注前列腺素E1(PGE1) 质量研究．中国临床药理学杂质
[14] Ming-Thau Sheu,Investigation of the percutaneous penetration of prostaglandin E1 and its alkyl ester.Journal of Controlled Release 55(1998) 153~160．
[15] 中国药典2000年版二部 附录XIXC药物稳定性指导原则附录197-附录200．
[16] Horst Schweer,Jochen Kammer,et,simultaneous determination of prostanoids in plasma by gas chromatography-negative-ion chemical-ionization mass spectrometry,journal of chromatography,338(1985) :273-280．
[17] W.H.HESSE,H.SCHWEER,H.W.SEYBERTH.separation and determination of prostaglandin E1 metabolites by high-performance liquid chromatography.Journal of chromatography.533(1990) :159-165．