开发一种使用二甲基乙酰胺和新型共处理赋形剂的非诺贝特固体超饱和自乳化前体（S-超 SNEP）。

Development of a solid supersaturated self-nanoemulsifying preconcentrate (S-superSNEP) of fenofibrate using dimethylacetamide and a novel co-processed excipient.

机构信息

a Department of Pharmaceutical Sciences , College of Pharmacy and Health Sciences, St. John's University , New York , USA.

出版信息

Drug Dev Ind Pharm. 2019 Mar;45(3):405-414. doi: 10.1080/03639045.2018.1546311. Epub 2018 Dec 2.

DOI:10.1080/03639045.2018.1546311

PMID:30444435

Abstract

BACKGROUND

Recrystallization of drug and incomplete drug release from liquisolid formulation are two major hurdles in the development of a supersaturated self-nanoemulsifying drug delivery system. The aim of this research work was to develop a solid supersaturated self-nanoemulsifying drug delivery system of fenofibrate (FB) for enhanced dissolution.

METHODS

FB loaded supersaturated self-nanoemulsifying preconcentrate (superSNEP) was prepared using dimethyl acetamide (DMA), medium chain triglycerides (MCT), and kolliphor EL. Co-processed excipients (CPE) prepared using inorganic microporous silica (Neusilin US2, Florite 100, or Aerosil 200) and hydrophilic polymers (Polyvinyl alcohol, HPMC, and Kollidon VA64) were evaluated for flow property, BET surface area, and adsorption capacity. Lipophilic fluorescent probe (coumarin-6) was used to investigate the extent of self-emulsification. The formulation was further characterized for solid state, in-vitro cytotoxicity in caco-2 cell line and in-vitro dissolution in a sink and non-sink conditions.

RESULTS

Optimized superSNEP with 20% w/v FB loading spontaneously formed nanoglobules of 40 ± 2.7 nm. DMA based self-nanoemulsifying system was found to be nontoxic to Caco-2 cell even at a very high concentration. CPE prepared using PVA and Florite 100 (1:1 weight ratio) showed the highest adsorption capacity (1 mL/g) and complete release of oil as depicted by fluorescence study. DSC thermogram and PXRD of S-superSNEP confirmed that FB remained in a solubilized state. S-superSNEP showed significantly faster and higher dissolution of FB in sink and non-sink conditions compared to the plain API.

CONCLUSION

DMA and PVA-F100 based novel co-processed excipient could be potentially useful for the development of solid supersaturated self-nanoemulsifying drug delivery system for enhancing dissolution of lipophilic drugs.

摘要

背景

药物重结晶和液体制剂中药物不完全释放是开发超饱和自微乳给药系统的两大障碍。本研究旨在开发一种固体超饱和自微乳给药系统（superSNEP）以提高非诺贝特（FB）的溶出度。

方法

采用二甲基乙酰胺（DMA）、中链甘油三酯（MCT）和聚氧乙烯氢化蓖麻油（Kolliphor EL）制备 FB 超饱和自微乳前体（superSNEP）。采用无机微孔硅（Neusilin US2、Florite 100 或 Aerosil 200）和亲水性聚合物（聚乙烯醇、HPMC 和 Kollidon VA64）制备共处理赋形剂（CPE），并考察其流动性能、BET 比表面积和吸附能力。采用亲脂性荧光探针（香豆素-6）考察自乳化程度。进一步对制剂进行固态、Caco-2 细胞系的体外细胞毒性和在溶出介质和非溶出介质中的体外溶出度进行表征。

结果

载药量为 20% w/v 的优化 superSNEP 可自发形成 40±2.7nm 的纳米球。基于 DMA 的自微乳体系即使在很高的浓度下也对 Caco-2 细胞无毒性。以 PVA 和 Florite 100（1:1 重量比）制备的 CPE 显示出最高的吸附能力（1mL/g）和荧光研究显示完全释放油相。DSC 热谱和 PXRD 表明 S-superSNEP 中 FB 仍处于溶解状态。与原料药相比，S-superSNEP 在溶出介质和非溶出介质中均表现出更快、更高的 FB 溶出度。