目的 合成帕利哌酮（PPD）的水溶性前體藥物，使其能通過離子導(dǎo)入技術(shù)快速透過皮膚。方法 合成PPD的水溶性前體藥物，即PPD的β-丙氨酸酯（PPD-β-Ala），并對前藥進(jìn)行結(jié)構(gòu)確證；利用高效液相色譜（HPLC）建立PPD及PPD-β-Ala的定量分析方法，并進(jìn)行方法學(xué)驗(yàn)證；測定PPD及PPD-β-Ala的飽和溶解度，并對PPD-β-Ala的脂水分配系數(shù)（P_o/w）和pKa進(jìn)行考察；進(jìn)行PPD-β-Ala體外透皮實(shí)驗(yàn)，包括被動(dòng)透皮吸收和離子導(dǎo)入透皮研究；在體外離子導(dǎo)入研究中，考察給藥池介質(zhì)[純水、HEPES溶液（pH 5.5）或HEPES溶液（pH 6.5）]、給藥池藥物濃度（10、20、30 mmol·L^-1）和電流密度（0.1、0.3、0.5 mA·cm^-2）對PPD-β-Ala透皮遞送量的影響。結(jié)果 前體藥物PPD-β-Ala結(jié)構(gòu)通過核磁共振氫譜得以確證。建立的HPLC法可對PPD及PPD-β-Ala同時(shí)檢測，方法專屬性、精密度和檢測限均滿足實(shí)驗(yàn)要求。PPD-β-Ala在純水中的飽和溶解度為33.46 mmol·L^-1，遠(yuǎn)高于PPD的水溶解度；PPD-β-Ala的lg P_o/w小于PPD；PPD-β-Ala可充分質(zhì)子化，帶1個(gè)正電荷，PPD不具備易解離或易質(zhì)子化的基團(tuán)。PPD-β-Ala不易透皮吸收，但在離子導(dǎo)入條件下可在接收池中檢出大量PPD-β-Ala，如在施加電流0.5 mA·cm^-2條件下，當(dāng)給藥池中PPD-β-Ala的濃度為30 mmol·L^-1時(shí)，7 h后的累積透皮遞送量可達(dá)250 nmol·cm^-2。所選給藥池介質(zhì)的變化未對PPD-β-Ala的累積透皮遞送量產(chǎn)生明顯改變，但給藥池藥物濃度和電流強(qiáng)度的增加均能提高PPD-β-Ala的累積透皮遞送量。在體外離子導(dǎo)入研究各組中均發(fā)現(xiàn)大量的PPD和PPD-β-Ala蓄積于皮膚，以0.5 mA·cm^-2電流強(qiáng)度、給藥池藥物濃度為20 mmol·L^-1（HEPES溶液為介質(zhì)，pH 5.5）的給藥條件為例，蓄積于皮膚中的PPD和PPD-β-Ala的量分別可達(dá)（144.21±41.73）、（890.61±106.40） nmol·cm^-2。結(jié)論 水溶性離子化的PPD前藥PPD-β-Ala可在離子導(dǎo)入過程中通過電遷移作用快速透皮，理論上可利用尺寸適中的離子導(dǎo)入透皮貼片滿足PPD的最小日給藥劑量。

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

國家自然科學(xué)基金資助項(xiàng)目（81603044）