Development of Metronidazole Loaded Chitosan Nanoparticles Using QbD Approach-A Novel and Potential Antibacterial Formulation.

Nagaraja Sreeharsha,Katharigatta N Venugopala,Rakesh K Tekade,Muktika Tekade,Anroop B Nair,Dnyaneshwar Kalyane,Kuldeep Rajpoot

doi:10.3390/pharmaceutics12100920

Abstract

The aim of this study was to design, optimize, and develop metronidazole (Met) loaded nanoparticles (MetNp) by employing quality-based design (QbD) as well as a risk assessment methodology. A fractional factorial design was used by selecting five independent variables viz., chitosan concentration, tripolyphosphate concentration, and acetic acid concentration as material attributes, stirring speed, and stirring time as process parameters, whereby their influence on two dependent variables such as particle size (PS) and %entrapment efficiency (%EE) was studied. MetNp were synthesized by employing an ionic-gelation technique and optimized formula obtained from the QbD design study. PS and %EE studies revealed the formation of MetNp with 558.06 ± 2.52 nm and 59.07 ± 2.15%, respectively. Furthermore, a Met release study in various simulated gastro-intestinal media suggested pH-triggered (pH > 7.0) and sustained release profile of Met from Eudragit S100 enteric-coated MetNp capsule (MetNp cap). Moreover, the stability investigation of formulations confirmed good stability with respect to their PS and residual drug content (RDC) at different temperature conditions. In conclusion, the QbD method was effectively utilized in the development of MetNp and enteric-coated MetNp cap depicting their potential to release Met through MetNp cap only in the colon region and can be utilized for the treatment of amoebiasis in the colon.

Highlights

Entamoeba (E.) histolytica is a protozoan parasite, which exists as a single-cell
During the preliminary investigation of CH NPs (CH-NPs) preparation, it was found that variables including the concentration of CH, TPP, and acetic acid; stirring time; and stirring speed affected the development of formulations
Due to the large number of variables, it is not beneficial to choose an Response Surface Methodology (RSM) methodology directly, which increases the experimental runs, time, and cost of experiments. These limitations can be overcome by applying 2-level fractional factorial design (FFD) to screen out significant factors that affect critical quality attributes (CQA), and after, this optimization can be carried out using the RSM method

Summary

Introduction

Entamoeba (E.) histolytica is a protozoan parasite, which exists as a single-cell. It is responsible for instigating amoebiasis in the large intestine. For the treatment of amoebiasis in the intestine, two drugs, namely metronidazole (Met) [2] and tinidazole [3], are widely used. To attain maximum effect against E. histolytica, these drugs should be delivered selectively in the colon region where the trophozoites live and grow [4]. Met is the preferred antibiotic for the treatment of intestinal amoebiasis (Figure 1a) [5]. The mechanism of the treatment is not fully understood, but involves the inhibition of DNA synthesis and the breaking of DNA into a single-strand by the oxidation, which is generally responsible for the killing of cells [6]. Met is not well suited to oral delivery, as it is absorbed completely within a small-time and obtains peak plasma concentrations after 1–2 h [6]

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Conclusion