香芹醇酯类衍生物经皮促透作用及其可逆性评价
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摘要
本课题以香芹醇(CV)为先导化合物,合成了8个新型脂肪酸香芹醇酯类衍生物,利用1H-NMR、MS确证了目标产物的结构。对合成的香芹醇酯类衍生物的基本化学特征参数进行计算,包括溶解度参数和油/水分配系数。应用减重法研究香芹醇酯类衍生物的挥发性,发现香芹醇成酯后其挥发性几乎消失。
应用不同脂溶性与酸碱性的模型药物包括具有较大油水分配系数的吲哚美辛(IM,酸性)、中等油水分配系数的硝酸异山梨酯(ISDN,中性)及较小油水分配系数的5—氟脲嘧啶(FU,碱性),全面评价香芹醇酯类衍生物在肉豆蔻酸异丙酯中的经皮吸收促透活性。研究发现香芹醇酯碳链长度为C8-C12时促透作用最强,并且促透剂角质层滞留量与其经皮促透活性呈抛物线型关系。
以双氯芬酸二乙胺(DDE)为模型药物,考察香芹醇酯类衍生物在贴剂中的经皮促透作用,寻找在压敏胶分散型贴剂中有显著促透作用的香芹醇酯。结果表明,香芹醇十二酸酯(C-DOD)在贴剂中是促透作用最强的促透剂。以大鼠为实验动物,进行DDE贴剂的体内药动学实验,比较C-DOD和CV在DDE贴剂中的体内经皮促透作用,并利用WinNonlin(?)软件中的IVIVC模块进行去卷积运算,以对DDE经皮吸收贴剂的体内外相关性进行相关性评价。结果表明,CV和C-DOD对贴剂中DDE的体内经皮吸收和体外经皮透过的促透作用相关性良好。
通过组织学评价和细胞毒性实验,初步评价CV和C-DOD的安全性。结果表明,大鼠皮肤经CV或C-DOD处理后未见明显病理改变,但CV的细胞毒性具有浓度依赖性,而C-DOD在试验浓度下无细胞毒性,提示C-DOD的安全性比CV高。
采用激光扫描共聚焦显微镜(CLSM)和衰减全反射红外(ATR-FTIR)技术研究香芹醇酯类衍生物促透机理,发现香芹醇酯类衍生物能够扰乱角质层脂质C-H侧链的有序性,增加脂质流动性,能够提高药物在角质层脂质中的分布,促进药物向皮肤深层渗透。
以离体皮肤通透性为指标,通过体外透皮实验和体外经皮水分散失实验确定皮肤屏障功能恢复时间。结果表明,CV移除后,大鼠皮肤的通透性迅速降低,8h后恢复正常。与CV相比,C-DOD作用过的大鼠皮肤屏障功能恢复较慢,但24h后也能恢复正常。以ATR-FTIR特征峰位变化为指标,通过测定促透剂移除后皮肤ATR-FTIR图谱特征峰位变化来确定皮肤屏障功能恢复时间。结果表明,CV和C-DOD处理后发生蓝移的C-H振动峰在4h后恢复到原来的峰位。以上结果提示CV和C-DOD经皮促透作用具有可逆性。
Eight l-carvyl esters were synthesized from l-carveol (CV) and fatty acids (C7-C18) and confirmed by1HNMR and MS in this study. The physicochemical parameters of the l-carvyl esters such as solubility parameter, and n-octanol/water partition coefficient were calculated by the approaches of Hoftyzer/Van Krevelen or by ACD/Labs software. Volatility of l-carvyl esters was evaluated by the live weight-loss experiments and l-carvyl esters exhibited no volatility.
The enhancing effects of l-carvyl esters on three drugs, indomethacin (IM, acid), isosorbide dinitrate (ISDN, neutrality) and5-fluorouracil (5-FU, base), which were selected based on their lipophilicity, were investigated by the in vitro permeation experiment using rat skin.l-Carvyl esters with a chain length of C8-C12were proved to be more potential enhancers than CV. An evident parabolic relationship was found between the permeation enhancement and the stratum corneum uptake of the l-carvyl esters.
Diclofenac diethylamine (DDE) was selected as a model drug to screen the most promising enhancer among l-carvyl esters which were applied in the dug in adhesive patches. The in vitro permeation studies indicated that l-carvyl dodecanoate (C-DOD) was the most promising enhancer in patch for DDE transdermal delivery. The in vivo studies in rats were conducted in order to compare the in vivo enhancing effect of C-DOD and CV on the skin permeation of DDE from patches. The in vitro/in vivo correlation (IVIVC) study of the patch was evaluated using the IVIVC Wizard in WinNonlin(?) program. The results suggested that the in vivo enhancing effect of l-carvyl esters was in accordance with that in vitro.
Histological experiments and cytotoxicity assays were applied to exam the irritation of CV and C-DOD. The results of histological experiments revealed that no histological change in rat skin was examined after pretreatment with CV and C-DOD. The results of cytotoxicity assays showed that CV had a concentration-dependent cytotoxicity, while C-DOD had no significant influence (p>0.05) on cell viability. These results indicated that C-DOD were safer than CV.
Confocal laser scanning microscopy (CLSM) and ATR-FTIR were employed to study the mechanism of skin permeation enhancement. The results suggested that l-carvyl esters could disrupt the order of the stratum corneum lipid C-H side chain. And as a result, the fluidity of SC lipid increased and the amount of drug distributed in the SC lipid increased, which was benefit for drug penetration into deeper layer.
Post-recovery skin permeability after removal of CV and C-DOD were examined using in vitro skin permeation study and in vivo transepidermal water loss determination. After removal of CV, the skin barrier function recovered in8h. While for C-DOD, the skin barrier function was not restored until C-DOD was removed for24h. In addition, post-recovery procedure of the skin barrier was also recorded using ATR-FTIR. After removal of CV and C-DOD for4h, the blue-shift C-H stretching peaks were restored. Thus, it was demonstrated that the enhancing effect of CV and C-DOD were all reversible.
应用不同脂溶性与酸碱性的模型药物包括具有较大油水分配系数的吲哚美辛(IM,酸性)、中等油水分配系数的硝酸异山梨酯(ISDN,中性)及较小油水分配系数的5—氟脲嘧啶(FU,碱性),全面评价香芹醇酯类衍生物在肉豆蔻酸异丙酯中的经皮吸收促透活性。研究发现香芹醇酯碳链长度为C8-C12时促透作用最强,并且促透剂角质层滞留量与其经皮促透活性呈抛物线型关系。
以双氯芬酸二乙胺(DDE)为模型药物,考察香芹醇酯类衍生物在贴剂中的经皮促透作用,寻找在压敏胶分散型贴剂中有显著促透作用的香芹醇酯。结果表明,香芹醇十二酸酯(C-DOD)在贴剂中是促透作用最强的促透剂。以大鼠为实验动物,进行DDE贴剂的体内药动学实验,比较C-DOD和CV在DDE贴剂中的体内经皮促透作用,并利用WinNonlin(?)软件中的IVIVC模块进行去卷积运算,以对DDE经皮吸收贴剂的体内外相关性进行相关性评价。结果表明,CV和C-DOD对贴剂中DDE的体内经皮吸收和体外经皮透过的促透作用相关性良好。
通过组织学评价和细胞毒性实验,初步评价CV和C-DOD的安全性。结果表明,大鼠皮肤经CV或C-DOD处理后未见明显病理改变,但CV的细胞毒性具有浓度依赖性,而C-DOD在试验浓度下无细胞毒性,提示C-DOD的安全性比CV高。
采用激光扫描共聚焦显微镜(CLSM)和衰减全反射红外(ATR-FTIR)技术研究香芹醇酯类衍生物促透机理,发现香芹醇酯类衍生物能够扰乱角质层脂质C-H侧链的有序性,增加脂质流动性,能够提高药物在角质层脂质中的分布,促进药物向皮肤深层渗透。
以离体皮肤通透性为指标,通过体外透皮实验和体外经皮水分散失实验确定皮肤屏障功能恢复时间。结果表明,CV移除后,大鼠皮肤的通透性迅速降低,8h后恢复正常。与CV相比,C-DOD作用过的大鼠皮肤屏障功能恢复较慢,但24h后也能恢复正常。以ATR-FTIR特征峰位变化为指标,通过测定促透剂移除后皮肤ATR-FTIR图谱特征峰位变化来确定皮肤屏障功能恢复时间。结果表明,CV和C-DOD处理后发生蓝移的C-H振动峰在4h后恢复到原来的峰位。以上结果提示CV和C-DOD经皮促透作用具有可逆性。
Eight l-carvyl esters were synthesized from l-carveol (CV) and fatty acids (C7-C18) and confirmed by1HNMR and MS in this study. The physicochemical parameters of the l-carvyl esters such as solubility parameter, and n-octanol/water partition coefficient were calculated by the approaches of Hoftyzer/Van Krevelen or by ACD/Labs software. Volatility of l-carvyl esters was evaluated by the live weight-loss experiments and l-carvyl esters exhibited no volatility.
The enhancing effects of l-carvyl esters on three drugs, indomethacin (IM, acid), isosorbide dinitrate (ISDN, neutrality) and5-fluorouracil (5-FU, base), which were selected based on their lipophilicity, were investigated by the in vitro permeation experiment using rat skin.l-Carvyl esters with a chain length of C8-C12were proved to be more potential enhancers than CV. An evident parabolic relationship was found between the permeation enhancement and the stratum corneum uptake of the l-carvyl esters.
Diclofenac diethylamine (DDE) was selected as a model drug to screen the most promising enhancer among l-carvyl esters which were applied in the dug in adhesive patches. The in vitro permeation studies indicated that l-carvyl dodecanoate (C-DOD) was the most promising enhancer in patch for DDE transdermal delivery. The in vivo studies in rats were conducted in order to compare the in vivo enhancing effect of C-DOD and CV on the skin permeation of DDE from patches. The in vitro/in vivo correlation (IVIVC) study of the patch was evaluated using the IVIVC Wizard in WinNonlin(?) program. The results suggested that the in vivo enhancing effect of l-carvyl esters was in accordance with that in vitro.
Histological experiments and cytotoxicity assays were applied to exam the irritation of CV and C-DOD. The results of histological experiments revealed that no histological change in rat skin was examined after pretreatment with CV and C-DOD. The results of cytotoxicity assays showed that CV had a concentration-dependent cytotoxicity, while C-DOD had no significant influence (p>0.05) on cell viability. These results indicated that C-DOD were safer than CV.
Confocal laser scanning microscopy (CLSM) and ATR-FTIR were employed to study the mechanism of skin permeation enhancement. The results suggested that l-carvyl esters could disrupt the order of the stratum corneum lipid C-H side chain. And as a result, the fluidity of SC lipid increased and the amount of drug distributed in the SC lipid increased, which was benefit for drug penetration into deeper layer.
Post-recovery skin permeability after removal of CV and C-DOD were examined using in vitro skin permeation study and in vivo transepidermal water loss determination. After removal of CV, the skin barrier function recovered in8h. While for C-DOD, the skin barrier function was not restored until C-DOD was removed for24h. In addition, post-recovery procedure of the skin barrier was also recorded using ATR-FTIR. After removal of CV and C-DOD for4h, the blue-shift C-H stretching peaks were restored. Thus, it was demonstrated that the enhancing effect of CV and C-DOD were all reversible.
引文
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