Solidified SNEDDS for the oral delivery of rifampicin: Evaluation, proof of concept, in vivo kinetics, and in silico GastroPlus™ simulation
Solidified SNEDDS for the oral delivery of rifampicin: Evaluation, proof of concept, in vivo kinetics, and in silico GastroPlus™ simulation
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DOI：
10.1016/j.ijpharm.2019.05.061
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发表时间：
2019-07-20
影响因子：
5.8
通讯作者：
Christoper, G. V. Peter
中科院分区：
文献类型：
--
作者：
Hussain, Afzal;Shakeel, Faiyaz;Christoper, G. V. Peter
本研究旨在研制一种利福平(RIF)固化自纳米乳化给药系统(SNEDDS)(固化RIF-OF1)，用于体内外评价。对优化后的处方进行粉末流动特性、载药效率和体外溶出度(pH-1.2、6.8和7.4时)的测试。还进行了配伍研究。这些制剂还测试了血液相容性、肠道渗透性、组织病理学效应和体内药代动力学。此外，使用GstroPlus进行了计算机模拟研究。在不同的pH值下，根据溶出度曲线，我们观察到即时释放(T-85%在15分钟内)。这可能是由于拉布拉索尔辅助的RIF增溶。重组RIF-OF1体外溶血实验表明，与阳性对照(裂解和碎裂)相比，RIF-OF1的红细胞结构正常。通过活体渗透和活检研究，可以建立促进RIF肠道渗透的理论基础，这些成分被认为是生理安全的(活检研究证明了粘膜的正常解剖)。体外-体内相关性(IVIVC)PLUS模块的模拟表明，IVIVC体外释放和体内吸收之间有很好的相关性，预测的系统吸收接近96.5%。与RIF混悬液相比，固化SNEDDS显示出更好的药代动力学特征。固体RIF-SNEDDS是促进肠道渗透和口服生物利用度较好的载体。因此，它可能成为治疗结核病的传统给药系统的合适替代方案。
The present investigation was performed to develop a rifampicin (RIF)-loaded solidified self-nanoemulsifying drug delivery system (SNEDDS) (solidified RIF-OF1) for in vitro and in vivo evaluations. Optimized formulations were tested for their powder flow characteristics, loading efficiency, and in vitro dissolution (at pH-1.2, 6.8 and 7.4). Compatibility studies were also performed. The formulations were also tested for hemocompatibility, intestinal permeation, histopathological effects, and in vivo pharmacokinetics. Additionally, an in silico simulation study using GastroPlus was performed. At different varied pH values, we observed immediate release (T-85% within 15 min) based on the dissolution profile. This could be due to labrasol-assisted RIF solubilization. In vitro hemolysis study of the reconstituted RIF-OF1 revealed normal architecture of erythrocytes compared to the positive control (lysed and fragmented). Through in vivo permeation and biopsy studies, a rationale for facilitated intestinal permeation of RIF with components deemed physiological safe (normal anatomy of mucosal membrane evidenced from biopsy study) could be established. The in vitro-in vivo correlation (IVIVC) plus module of GastroPlus (TM) simulation showed a good IVIVC between in vitro release and in vivo absorption with a predicted systemic absorption of similar to 96.5%. Solidified SNEDDS showed improved pharmacokinetic profiles compared to RIF suspension. Solid RIF-SNEDDS was demonstrated to be a suitable carrier for enhanced intestinal permeation and oral bioavailability. Hence, it may serve as a suitable alternative to conventional delivery systems for tuberculosis treatment.