水溶性帕利哌酮前体药物的合成及其体外透皮研究  

Synthesis of a water-soluble prodrug of paliperidone and investigation into its transdermal delivery in vitro

作　　者：顾薇 王晨慧 刘小卫 周烨 包小峰 陈勇 GU Wei;WANG Chenhui;LIU Xiaowei;ZHOU Ye;BAO Xiaofeng;CHEN Yong(Department of Clinical Pharmacy,The Second People's Hospital of Nantong,Nantong 226002,China;School of Pharmacy,Nantong University,Nantong 226001,China)

机构地区：[1]南通市第二人民医院临床药学部,江苏南通226002 [2]南通大学药学院,江苏南通226001

出　　处：《药物评价研究》2022年第10期2008-2016,共9页Drug Evaluation Research

基　　金：国家自然科学基金资助项目(81603044)。

摘　　要：目的合成帕利哌酮(PPD)的水溶性前体药物,使其能通过离子导入技术快速透过皮肤。方法合成PPD的水溶性前体药物,即PPD的β-丙氨酸酯(PPD-β-Ala),并对前药进行结构确证;利用高效液相色谱(HPLC)建立PPD及PPD-β-Ala的定量分析方法,并进行方法学验证;测定PPD及PPD-β-Ala的饱和溶解度,并对PPD-β-Ala的脂水分配系数(P_(o/w))和pKa进行考察;进行PPD-β-Ala体外透皮实验,包括被动透皮吸收和离子导入透皮研究;在体外离子导入研究中,考察给药池介质[纯水、HEPES溶液(pH 5.5)或HEPES溶液(pH 6.5)]、给药池药物浓度(10、20、30 mmol·L^(-1))和电流密度(0.1、0.3、0.5 mA·cm^(−2))对PPD-β-Ala透皮递送量的影响。结果前体药物PPD-β-Ala结构通过核磁共振氢谱得以确证。建立的HPLC法可对PPD及PPD-β-Ala同时检测,方法专属性、精密度和检测限均满足实验要求。PPD-β-Ala在纯水中的饱和溶解度为33.46 mmol·L^(-1),远高于PPD的水溶解度;PPD-β-Ala的lg P_(o/w)小于PPD;PPD-β-Ala可充分质子化,带1个正电荷,PPD不具备易解离或易质子化的基团。PPD-β-Ala不易透皮吸收,但在离子导入条件下可在接收池中检出大量PPD-β-Ala,如在施加电流0.5 mA·cm^(−2)条件下,当给药池中PPD-β-Ala的浓度为30 mmol·L^(-1)时,7 h后的累积透皮递送量可达250 nmol·cm^(−2)。所选给药池介质的变化未对PPD-β-Ala的累积透皮递送量产生明显改变,但给药池药物浓度和电流强度的增加均能提高PPD-β-Ala的累积透皮递送量。在体外离子导入研究各组中均发现大量的PPD和PPD-β-Ala蓄积于皮肤,以0.5 mA·cm^(−2)电流强度、给药池药物浓度为20 mmol·L^(-1)(HEPES溶液为介质,pH 5.5)的给药条件为例,蓄积于皮肤中的PPD和PPD-β-Ala的量分别可达(144.21±41.73)、(890.61±106.40)nmol·cm^(−2)。结论水溶性离子化的PPD前药PPD-β-Ala可在离子导入过程中通过电迁移作用快速透皮,理论上可利用尺寸适�Objective To synthesize a water-soluble prodrug of paliperidone(PPD)in order to make it rapidly penetrate the skin by iontophoresis.Methods The water-soluble prodrug of PPD,i.e.,β-alanine ester of PPD(PPD-β-Ala),was synthesized,and the structure of the prodrug was confirmed.The analytical method to quantify PPD and PPD-β-Ala was developed by high performance liquid chromatography(HPLC),and the method was validated.The saturated solubility of PPD and PPD-β-Ala was determined,and the oil-water partition coefficient(P_(o/w))and pKa of PPD-β-Ala were investigated.Transdermal delivery of PPD-β-Ala was investigated in vitro,including passive and iontophoretic transdermal delivery studies.In the iontophoretic study,the effects of matrix[pure water,HEPES solution(pH 5.5)or HEPES solution(pH 6.5)]in the donor compartment,the drug concentration(10,20,and 30 mmol·L^(-1))in donor compartment and the current density(0.1,0.3,and 0.5 mA·cm^(−2))applied on the transdermal delivery of PPD-β-Ala were investigated in vitro.Results The structure of PPD-β-Ala was confirmed by proton magnetic resonance spectroscopy.The analytical method using HPLC can simultaneously quantify PPD and PPD-β-Ala,and the method specificity,precision and limit of detection meet the experimental requirements.The saturated solubility of PPD-β-Ala in pure water was approximately 33.46 mmol·L^(-1),which was much higher than that of PPD.The lg P_(o/w)of PPD-β-Ala was less than that of PPD.PPDβ-Ala can be fully protonated and has a positive charge.PPD has no easily dissociated or protonated groups.PPD-β-Ala was not well absorbed via the skin,but appreciable amounts of PPD-β-Ala can be detected in the receiver compartment under iontophoresis.For example,the cumulative transdermal delivery of PPD-β-Ala could reach 250 nmol·cm^(−2)when a current of 0.5 mA·cm^(−2) was applied in the donor compartment containing 30 mmol·L^(-1)of PPD-β-Ala for 7 h.The selected media in donor compartment did not impact the cumulative delivery of PPD-β-Ala s

关 键 词：帕利哌酮 透皮给药 离子导入 水溶性前药 精神分裂症 

分 类 号：R944.9[医药卫生—药剂学]