Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan.
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Pharm Res. 2022 May;39(5):977-987. doi: 10.1007/s11095-022-03276-0. Epub 2022 May 2.
This study aims to understand the process and mechanism of oral drug absorption from liposomes and to verify the usefulness of liposomal formulation for poorly soluble drugs.
Cyclosporine A (CsA) was used as a model drug and entrapped into Dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) liposomes. Molecular state of CsA in the liposomes was analyzed using powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). Release profiles of CsA from liposomes were observed in fasted state simulated intestinal fluid (FaSSIF). Oral absorption of CsA from liposomal formulations were investigated in rats.
PXRD and PLM analyses suggested that CsA exists in the lipid layer of liposomes as a molecular dispersed state. Although both liposomes retained CsA stably in the simple buffer, DPPC liposomes quickly released CsA within 10 min in FaSSIF due to the interaction with bile acid. In contrast, effect of bile acid was negligible in DSPC, indicating a high resistivity to membrane perturbation. Oral bioavailability of CsA from liposomal formulations were almost comparable with that from a marketed product (Neoral). However, the absorption profiles were clearly different. CsA was absorbed quickly from DPPC liposomes and Neoral, while sustained absorption profile was observed from DSPC liposomes. Further study in which ritonavir was co-entrapped in the liposomes with CsA showed the higher efficacy of ritonavir to increase oral bioavailability of CsA.
Liposomes allows the appropriate formulation design for oral delivery of poorly soluble drugs, not only to increase the extent but also to control the rate of absorption.
本研究旨在了解脂质体中口服药物吸收的过程和机制，并验证脂质体制剂对难溶性药物的有效性。
环孢素 A（CsA）被用作模型药物并包封在二棕榈酰磷脂酰胆碱（DPPC）和二硬脂酰磷脂酰胆碱（DSPC）脂质体中。使用粉末 X 射线衍射（PXRD）和偏光显微镜（PLM）分析 CsA 在脂质体中的分子状态。在禁食状态模拟肠液（FaSSIF）中观察 CsA 从脂质体中释放的情况。在大鼠体内研究了 CsA 从脂质体制剂中的口服吸收情况。
PXRD 和 PLM 分析表明，CsA 以分子分散状态存在于脂质体的脂质层中。尽管两种脂质体在简单缓冲液中都能稳定地保留 CsA，但 DPPC 脂质体在 FaSSIF 中由于与胆汁酸相互作用，在 10 分钟内迅速释放 CsA。相比之下，胆汁酸对 DSPC 的影响可以忽略不计，表明其对膜扰动具有高度抵抗力。CsA 从脂质体制剂中的口服生物利用度几乎与市售产品（Neoral）相当。然而，吸收曲线明显不同。CsA 从 DPPC 脂质体和 Neoral 中快速吸收，而从 DSPC 脂质体中观察到持续的吸收曲线。进一步的研究表明，当利托那韦与 CsA 共同包封在脂质体中时，利托那韦可以提高 CsA 的口服生物利用度。
脂质体允许对难溶性药物的口服递送进行适当的制剂设计，不仅可以增加程度，还可以控制吸收速度。
