A potent preparation method combining neutralization with microfluidization for rebamipide nanosuspensions and its in vivo evaluation

Abstract

Backgrounds: Rebamipide (REB) is classified as a Biopharmaceutics Classification System (BCS) Class-IV compound with poor aqueous solubility and poor permeability. The local concentration in the mucosa makes REB exhibiting the therapeutic activities, and the strategy of increasing the dissolution rate has the possibility to improve the oral gastrointestinal (GI) distribution when using REB nanosuspensions.

Objective: The purpose of this work was to prepare REB nanosuspensions (REB-NSs) by combining neutralization with microfluidization to improve its dissolution rate and orally pharmacokinetic properties.

Methods: The feasibility of using acid-base neutralization and microfluidization to prepare REB-NSs was studied, and the preparation was optimized by central composite design (CCD). Physical states were characterized by using some technical methods, while the plasma drug concentration and GI distribution in rodents were determined.

Results: The experimental results identified a formulation with 10 mg/mL REB, 0.9% (w/v) Lutrol F127, and 0.6% (w/v) Kollidon 90F. The dissolution rate of the dried REB-NSs was faster than that of Mucosta^® tablets in different media, and the pharmacokinetic study showed a slight increase (1.3-fold and 1.1-fold) in the AUC_{0–12 h} compared with unprocessed conventional suspensions (CSs) and solutions. Also, the GI distribution of REB-NSs improved compared with REB-CSs, and this would be preferable to assist in protecting GI mucosa.

Conclusion: The REB-NSs prepared by the combining method exhibited a higher plasma drug concentration and superior GI distribution, thereby demonstrating positive results for preparing nanosuspensions of local effective BCS IV drugs with pH dependence such as REB by this method.

Keywords::

• Rebamipide
• nanosuspensions
• acid-base precipitation
• microfluidization
• bioavailability
• gastrointestinal distribution

Acknowledgements

We are grateful to Dr. David B. Jack for the correcting of the manuscript.

Declaration of interest

Financial support from the National Basic Research Program of China (973 Program) (No. 2009CB930300). The authors report no conflict of interest. The authors alone will be responsible for the whole content and writing of this paper.