通过质量源于设计（QbD）方法制备并表征用于提高呋塞米溶出速率的稳定纳米混悬液

Preparation and Characterization of Stable Nanosuspension for Dissolution Rate Enhancement of Furosemide: A Quality by Design (QbD) Approach.

作者信息

Marzan Akbar L, Tabassum Rahnuma, Jahan Basarat, Asif Mehedi H, Reza Hasan M, Kazi Mohsin, Alshehri Sultan M, de Matas Marcel, Shariare Mohammad H

机构信息

Department of Pharmaceutical Sciences, North South University, Dhaka, Bangladesh.

Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

出版信息

Curr Drug Deliv. 2018;15(5):672-685. doi: 10.2174/1567201815666180123094320.

DOI:10.2174/1567201815666180123094320

PMID:29359667

Abstract

BACKGROUND

Nano drug delivery systems have the potential to address the challenges of delivering BCS Class II and IV drugs like furosemide. The purpose of the current study is to prepare stable nanosuspension and investigate in vitro dissolution performance of the model compound furosemide using quality by design (QbD) approach.

METHODS

Nanosuspension batches with uniform particle size were prepared for furosemide using the antisolvent precipitation method. A quality by design (Qbd) approach was explored to understand the impact of process parameters (stirring time, stirring speed, temperature, and injection rate) and material attributes (drug concentration, stabilizer type, drug: stabilizer ratio, and antisolvent: solvent ratio) on the quality attributes of furosemide nanosuspension using a full factorial experimental design. Multiple linear regression and ANOVA were employed to estimate and identify the critical process parameters and material attributes. Injection rate and stirring time were identified as the most critical process parameters' affecting the quality attributes of furosemide nanosuspension.

RESULTS

Individual material attributes did not show significant impact on the average particle size of the nanocrystals, however two-way interactions between material attributes (stabilizer type/drug concentration and stabilizer type/antisolvent: solvent ratio) significantly affected nanosuspension particle size distribution. Solid state characterization (PXRD, DSC and SEM) did not exhibit any changes of physical form during preparation and optimization of the furosemide nanosuspension. Dissolution of the furosemide nanocrystals in gastric media was significantly higher than that observed for micronized furosemide suspension and raw furosemide powder. Stability study data suggests that optimized batches of furosemide nanosuspensions were stable for three months at 4°C and ambient conditions.

CONCLUSION

The antisolvent precipitation method can produce stable furosemide nanosuspensions with desirable quality attributes and enhancement of dissolution rate in the gastric medium as compared to the raw furosemide powder and microsuspension.

摘要

背景

纳米药物递送系统有潜力应对递送像呋塞米这类BCS II类和IV类药物的挑战。本研究的目的是制备稳定的纳米混悬液，并采用质量源于设计（QbD）方法研究模型化合物呋塞米的体外溶出性能。

方法

采用反溶剂沉淀法为呋塞米制备粒径均匀的纳米混悬液批次。采用全因子实验设计，探索质量源于设计（QbD）方法，以了解工艺参数（搅拌时间、搅拌速度、温度和注入速率）和物料属性（药物浓度、稳定剂类型、药物：稳定剂比例以及反溶剂：溶剂比例）对呋塞米纳米混悬液质量属性的影响。采用多元线性回归和方差分析来估计和识别关键工艺参数和物料属性。注入速率和搅拌时间被确定为影响呋塞米纳米混悬液质量属性最关键的工艺参数。

结果

单个物料属性对纳米晶体的平均粒径未显示出显著影响，然而物料属性之间的双向相互作用（稳定剂类型/药物浓度以及稳定剂类型/反溶剂：溶剂比例）显著影响纳米混悬液的粒径分布。在呋塞米纳米混悬液的制备和优化过程中，固态表征（粉末X射线衍射、差示扫描量热法和扫描电子显微镜）未显示出物理形态的任何变化。呋塞米纳米晶体在胃介质中的溶出明显高于微粉化呋塞米混悬液和呋塞米原料药粉末。稳定性研究数据表明，优化后的呋塞米纳米混悬液批次在4°C和环境条件下可稳定保存三个月。