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中的离子导入透皮贴片满足PPD的最小日给药剂量。

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. PPD-β-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 significantly, but the increase in applied drug concentration and current intensity could enhance the cumulative delivery of PPD-β-Ala. It was found that appreciable amounts of PPD and PPD-β-Ala were deposited in the skin in each group. For example, the amount of PPD and PPD-β-Ala retained in the skin attained (144.21 ±41.73) and (890.61 ±106.40) nmol·cm^-2, respectively, when a current of 0.5 mA·cm^-2 was applied in the donor compartment containing 20 mmol·L^-1 of PPD-β-Ala (HEPES solution as medium, pH 5.5) for 7 h. Conclusion The water-soluble, ionizable PPD prodrug, i.e., PPD-β-Ala, can rapidly penetrate the skin by electromigration effect during iontophoresis. In theory, an iontophoretic transdermal patch with moderate size can be used to deliver minimum daily dose of PPD.

R944.9

国家自然科学基金资助项目（81603044）