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

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.

Study of Different Chitosan/Sodium Carboxymethyl Cellulose Proportions in the Development of Polyelectrolyte Complexes for the Sustained Release of Clarithromycin from Matrix Tablets

“…High electrostatic repulsion between CS chains (pKa 6.5) and the significant relaxation of CMC polymer chains (pKa > 3.5) were observed in 0.1 N HCl simulated gastric fluid [ 9 , 13 ]. Moreover, a significant increase in the solubility of CL at low pH [ 11 , 15 ] could explain these fast dissolution profiles [ 4 ]. These immediate release systems in a gastric medium (0.1 N HCl) demonstrate rapid degradation of CL and are not suitable for gastric treatment of Helicobacter pylori [ 11 ].…”

“…The electrostatic repulsion of the cationic groups and high matrix swelling allow uptake in the dissolution medium [ 1 ]. This process results in fast-disintegrating hydrogel tablets that favor rapid drug release [ 4 ]. The kinetic parameters of these hydrogel tablets could not be evaluated due to their fast dissolution.…”

“…Chitosan (CS) is the most widely used cationic polymer; it has good biocompatibility and is nontoxic and biodegradable [ 3 ]. Its molecular weight control and degree of deacetylation also allow its use in PECs for the sustained release of drugs [ 4 , 5 ].…”

“…Natural anionic polymers have been extensively used for the development of PECs [ 5 , 6 , 7 , 8 ]. However, anionic cellulose derivatives such as hypromellose phthalate [ 4 ] and carboxymethyl cellulose sodium [ 9 ] show greater control of the molecular weight and the number of carboxylic groups (COO − ). Carboxymethyl cellulose sodium (CMC) is a cellulose derivative with good solubility in water.…”

Application of biomaterials in the eradication of Helicobacter pylori: A bibliometric analysis and overview

“…Among mucosal adhesion polymers, deacetylated chitosan is intriguing due to its biodegradability, biological adhesion, and ability to enhance the uptake of active macromolecules ( Hejazi and Amiji, 2003 ). The -NH2 group of chitosan and its derivatives is protonated at the acidic pH of gastric juice and establishes electrostatic interactions with negatively charged gastric mucin and bacterial membranes, thereby exhibiting adhesion properties, and consequently has been developed recurrently for gastric applications ( Chaves de Souza et al, 2020 ; Lang et al, 2020 ). The lipophilic amino acid residues of maltolysin are capable of interacting with biological tissues, while maltolysin nanoparticles are susceptible to aggregation by pH, temperature, and salt, thus achieving their adhesion properties ( Arangoa et al, 2000 ).…”