CRV431负载自微乳化药物传递系统的开发，表征和药代动力学

StephenW

J Pharm Pharm Sci. 2018;21(1s):335s-348s. doi: 10.18433/jpps30245.
Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System.
Trepanier DJ1, Ure DR, Foster RT.
Author information

1
    ContraVir Pharmaceuticals Inc. Edmonton, Alberta, Canada.

Abstract
PURPOSE:

The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use.
METHODS:

The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).
RESULTS:

The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats.
CONCLUSIONS:

The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.

PMID:
    30472978

StephenW

J Pharm Pharm Sci。 2018; 21（1秒）：335S-348s。 doi：10.18433 / jpps30245。
CRV431负载自微乳化药物传递系统的开发，表征和药代动力学评估。
Trepanier DJ1，Ure DR，Foster RT。
作者信息

1
    ContraVir Pharmaceuticals Inc.埃德蒙顿，加拿大艾伯塔省。

抽象
目的：

本研究的目的是开发一种自微乳化药物递送系统（SMEDDS）制剂，用于口服递送CRV431，一种非免疫抑制性的环孢菌素A类似物。相对于环孢菌素A，CRV431难溶于脂质溶剂，因此呈现开发用于临床用途的足够口服生物利用度的制剂的挑战。
方法：

在一系列常用的表面活性剂，油和共溶剂中测定了环孢菌素衍生物CRV431的溶解度。从最可溶的赋形剂和原型制剂构建了伪三元相图，开发了系列1和系列2。使用液相色谱 - 电喷雾电离 - 质谱（LC-ESI-MS）在健康人志愿者中研究单次口服剂量1和3mg / kg CRV431 SMEDDS后的药代动力学。
结果：

SERIES 1制剂的最大载药量小于40 mg / ml。辅助比例的操作允许开发系列2制剂，与系列1相比，其具有更高的药物负载能力和CRV431的稳定性。进一步的改进允许开发含有高达90mg / ml CRV431的优化SMEDDS制剂，其中当分散到水性介质中时，产生微乳液平均粒径为25nm。优化的CRV431 SMEDDS的药代动力学显示出优异的人体全身暴露和剂量比例效应，以及大鼠肝脏中的高药物水平。
结论：

开发的SMEDDS制剂应该允许CRV431的有效临床开发，目标是治疗肝病，包括乙型肝炎（HBV），纤维化和肝细胞癌。

结论：
    30472978

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windu

这个药物进度太慢了