Design of Mucoadhesive Nanostructured Polyelectrolyte Complexes Based on Chitosan and Hypromellose Phthalate for Metronidazole Delivery Intended to the Treatment of Helicobacter pylori Infections.

Maurício Palmeira Chaves De Souza,Marlus Chorilli,Taís Maria Bauab,Matheus Aparecido Dos Santos Ramos,Fernanda Isadora Boni,Liliane Neves Pedreiro,Nathalia Helena De Mattos,Maria Palmira Daflon Gremião

doi:10.3390/pharmaceutics12121211

Maurício Palmeira Chaves De Souza, Marlus Chorilli + Show 6 more

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https://doi.org/10.3390/pharmaceutics12121211

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Abstract

Metronidazole (MT) is an important drug available for Helicobacter pylori infection treatment. However, in the past few years, this drug has presented effective reduction for infection control, one of the most important reasons is attributed to the reduction of retention time in the stomach environment. Mucoadhesive nanostructured polyelectrolyte complexes (nano PECs) based on chitosan (CS) and hypromellose phthalate (HP) were rationally developed using a full factorial design (21 × 21 × 31), for the incorporation of MT based on the enhancement of the antimicrobial potential against active Helicobacter pylori, in the stomach. Different mass ratios of CS:HP (w/w) were tested, reaching the most promising ratios of 1:0.1, 1:0.5, and 1:1, and two methods of polymers addition (pouring-I and drip-II) were also evaluated. From method I, the obtained particles presented a diameter in the range of 811–1293 nm (Z-average) and a polydispersity index (PDI) between 0.47 and 0.88. By method II, there was a significant reduction in diameter and PDI to 553–739 nm and 0.23 at 0.34, respectively. The drug incorporation also resulted in a reduction in the diameter and PDI of the nano PECs. All samples showed positive zeta potential, about 20 mV, and a high percentage of MT incorporation (±95%). The method factor presented a greater influence on the nano PECs characteristics. Interactions in the system constituents were indicated by the FTIR data. Nano PECs mucoadhesiveness was observed and the composition and charge density were responsible for this phenomenon. MT dissolution evaluation showed the similarity of the dissolution profiles of free and loaded MT, in which almost 100% of the drug was in the simulated gastric medium in 120 min of testing. The in vitro antimicrobial potential against H. pylori of loaded nano PECs were measured and the minimum inhibitory concentration observed for free MT was >2000 µg/mL, while for the incorporated MT lower values were observed, showing an increase in the encapsulated MT activity.

Highlights

Infections caused by Helicobacter pylori infections in stomach environment are the most prevalent infection diseases all over the world, affecting around half of the world’s population [1]
As the HP10 sample showed a high polydispersity index (PDI) value and decreased zeta potential, which may be indicative of low physical stability, it was discarded from the test of obtainment by method II
The gradual and slow addition of the polymer allows the conditions of thermodynamic equilibrium to be established to a greater extent, as in this case the system has greater conformational and configurational freedom, which should result in more intense interactions between CS and hypromellose phthalate (HP), resulting in smaller and homogeneous particles [44]

Summary

Introduction

Infections caused by Helicobacter pylori infections in stomach environment are the most prevalent infection diseases all over the world, affecting around half of the world’s population [1]. Several therapeutic schemes based in the use of drugs with antibacterial potential has been employed for the treatment of H. pylori infections. One of the therapeutic strategies is the triple therapy, consisting of a proton pump inhibitor and two antibiotics: amoxicillin, clarithromycin, or metronidazole (MT) [3]. The use of this drug association is effective to eradicate almost 91% of the bacterial load [4]. The triple therapy is the most efficient therapeutic approach, the bacterial resistance to MT is more prevalent than with other antibiotics. In England, between 2000 and 2005, the MT resistance was reported in 25% of the evaluated clinical cases [5]

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