Zhou Ye, Wang Chenhui, Liu Wenqian, Yang Meiqing, Xu Bohui, Chen Yong
School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong 226001, China.
Pharmaceutics. 2022 Apr 19;14(5):889. doi: 10.3390/pharmaceutics14050889.
The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10 mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: T was 0.83 ± 0.29 h, and C was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer T and lower C. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia.
本研究的目的是开发一种用于帕利哌酮（PPD）的药物递送系统，以便为急性精神分裂症患者提供更有效的治疗策略。采用薄膜水化法制备了载有PPD的Soluplus/TPGS混合胶束（PPD-S/T-MM）。空白S/T-MM的临界胶束浓度（CMC）为4.77×10mg/mL。PPD在PPD-S/T-MM制剂中的溶解度远高于在纯水中的溶解度。空白或载药S/T-MM的粒径约为60nm。多分散指数（PDI）小于0.1。在透射电子显微镜下，PPD-S/T-MM呈现近球形。PPD-S/T-MM的包封率（EE%）高于94%。基于XRD和DSC分析，证明PPD以无定形分散体或固溶体形式掺入混合胶束的核心。PPD-S/T-MM在用水稀释和环境pH值变化时是稳定的。尽管PPD-S/T-MM在酸性溶液中释放PPD的速率低于PPD原料，但在中性条件下它们的释放速率比在相同中性条件下仅表现出适度溶解的PPD原料更快。这证明PPD-S/T-MM可以更可控地释放PPD。大鼠口服PPD-S/T-MM（PPD剂量为6mg/kg）后，PPD的血浆浓度迅速升高：达峰时间（Tmax）为0.83±0.29小时，峰浓度（Cmax）为844.33±93.73ng/mL。口服PPD混悬液导致Tmax延长和Cmax降低。PPD-S/T-MM相对于PPD混悬液的相对口服生物利用度约为158%。这些发现证实，与PPD原料相比，PPD-S/T-MM在中性条件下能提供更快的释放，在大鼠中具有更好的口服吸收，这可能对急性精神分裂症患者有益。
