Song Tingting, Wang Wenyu, Wu Yan, Liu Chaolong, Yuan Lu, Sun Zhihong, Zhang Jingjing, Sun Yong
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266071, People's Republic of China.
Department of Obstetrics and Gynecology, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao Hospital of Traditional Chinese Medicine, Qingdao, Shandong, 266033, People's Republic of China.
Int J Nanomedicine. 2025 Apr 16;20:4883-4901. doi: 10.2147/IJN.S512876. eCollection 2025.
Mental illness is the leading cause of the global burden of non-fatal disease. Lurasidone hydrochloride (LSD) is an important antipsychotic drug, but has poor water solubility and low oral bioavailability (9-19%). Additionally, LSD exhibits twice the positive food effect, meaning that patients need to consume 350 kcal when taking the medication, which leads to reduced adherence. In this study, we developed oral LSD liposome enteric-coated capsules to eliminate the food effect and improve the oral bioavailability of LSD.
Firstly, liposomes were prepared by cethanocl injection cmethod, and their morphology, particle size, polydispersity index, encapsulation efficiency, drug loading capacity, stability and in vitro release were characterized. Subsequently, the mucous permeability and transepithelial transport capacity of p-R8-DOCA-Lipos in intestinal epithelial cells were investigated, and the in vivo pharmacokinetics and biosafety of LSD liposome enteric-coated capsules were further studied.
p-R8-DOCA-Lipos had uniform morphology (particle size~112 nm), high encapsulation efficiency and drug loading capacity, and good stability in SIF. Cellular studies have shown that pHPMA gradually dissolved as it penetrated the mucus layer, and exposed R8-DOCA-Lipos facilitated cellular uptake. The cellular uptake and cumulative transepithelial transport of p-R8-DOCA-Lipos were 4.96 and 3.80 times higher than those in the solution group, respectively. The endocytosis of p-R8-DOCA-Lipos were mainly mediated by clathrin, caveolin and ASBT. Intracellular tracing showed that p-R8-DOCA-Lipos could achieve lysosomal escape, and ER and GA pathways were involved in their intracellular transport. In vivo pharmacokinetic studies have shown that AUC of p-R8-DOCA-Lipos under fasted and fed conditions were similar to that of LSD suspension under fed conditions, which reduced the food effect of LSD and improved patient compliance. Finally, they had good biosafety after continuous oral administration.
Therefore, p-R8-DOCA-Lipos may be a promising strategy for overcoming multiple gastrointestinal barriers to improve oral absorption of LSD.
精神疾病是全球非致命性疾病负担的主要原因。盐酸鲁拉西酮（LSD）是一种重要的抗精神病药物，但水溶性差，口服生物利用度低（9 - 19%）。此外，LSD呈现出两倍的阳性食物效应，这意味着患者在服药时需要摄入350千卡热量，从而导致依从性降低。在本研究中，我们开发了口服LSD脂质体肠溶胶囊，以消除食物效应并提高LSD的口服生物利用度。
首先，采用乙醇注入法制备脂质体，并对其形态、粒径、多分散指数、包封率、载药量、稳定性和体外释放进行表征。随后，研究了p-R8-DOCA-Lipos在肠上皮细胞中的黏液通透性和跨上皮转运能力，并进一步研究了LSD脂质体肠溶胶囊的体内药代动力学和生物安全性。
p-R8-DOCA-Lipos形态均匀（粒径约112 nm），包封率和载药量高，在模拟肠液中稳定性良好。细胞研究表明，pHPMA在穿透黏液层时逐渐溶解，暴露的R8-DOCA-Lipos促进细胞摄取。p-R8-DOCA-Lipos的细胞摄取和累积跨上皮转运分别比溶液组高4.96倍和3.80倍。p-R8-DOCA-Lipos的内吞作用主要由网格蛋白、小窝蛋白和ASBT介导。细胞内追踪显示，p-R8-DOCA-Lipos可以实现溶酶体逃逸，内质网和高尔基体途径参与其细胞内转运。体内药代动力学研究表明，p-R8-DOCA-Lipos在禁食和进食条件下的AUC与LSD混悬液在进食条件下相似，这降低了LSD的食物效应并提高了患者依从性。最后，连续口服给药后它们具有良好的生物安全性。
因此，p-R8-DOCA-Lipos可能是一种有前途的策略，可克服多种胃肠道屏障以改善LSD的口服吸收。
