Clarithromycin-Loaded Poly (Lactic-co-glycolic Acid) (PLGA) Nanoparticles for Oral Administration: Effect of Polymer Molecular Weight and Surface Modification with Chitosan on Formulation, Nanoparticle Characterization and Antibacterial Effects

Abstract

Clarithromycin (CLR) is a member of the macrolide antibiotic group. CLR has low systemic oral bioavailability and is a drug of class II of the Biopharmaceutical Classification System. In many studies, using nanoparticles (NPs) as a drug delivery system has been shown to increase the effectiveness and bioavailability of active drug substances. This study describes the development and evaluation of poly (lactic-co-glycolic acid) (PLGA) NPs and chitosan (CS)-coated PLGA NPs for oral delivery of CLR. NPs were obtained by nanoprecipitation technique and characterized in detail, and the effect of three molecular weights (Mw1: 7.000–17.000, Mw2: 38.000–54.000, Mw3: 50.000–190.000) of PLGA and CS coating on particle size (PS), zeta potential (ZP), entrapment efficiency (EE%), and release properties etc. were elucidated. Gastrointestinal stability and cryoprotectant effect tests were performed on the NPs. The PS of the prepared NPs were in the range of 178 to 578 nm and they were affected by the Mw and CS coating. In surface-modified formulations with CS, the ZP of the NPs increased significantly to positive values. EE% varied from 62% to 85%, depending upon the Mw and CS coating. In vitro release studies of CLR-loaded NPs showed an extended release up to 144 h. Peppas–Sahlin and Weibull kinetic model was found to fit best for CLR release from NPs. By the broth microdilution test method, the antibacterial activity of the formulations was determined on Staphylococcus aureus (ATCC 25923), Listeria monocytogenes (ATCC 1911), and Klebsiella pneumoniae (ATCC 700603). The structures of the formulations were clarified by thermal (DSC), FT-IR, and 1H-NMR analysis. The results showed that PS, ZP, EE%, and dissolution rates of NPs were directly related to the Mw of PLGA and CS coating.

Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing

“…However, the formulated isoniazid peak presented as a broad band, which can be related to physical transitioning from crystalline into amorphous structures attributable to solvation and encapsulation of drug molecules into the processed polymeric carrier. A significant change in heat flow from -36.4 mW (unformulated isoniazid) to -3.7 mW (isoniazid in RDS) (Figure 2b,c) was seen, further supporting the likely drug encapsulation in the amorphous state, coupled with stable molecular dispersions within the polymeric chains [24]. Overall, the thermograms (Figures 2a-c) demonstrate the absence of any destructive/irreversible physicochemical interactions between isoniazid and the excipients during the RDS preparation process.…”

“…A generally acceptable PDI value of 0.37 ± 0.04 was recorded for the RDS powder, indicating that the particles were mostly homogenous and well dispersed within the formulation. The measured ZP was −41.10 ± 5.57 mV, showing a stable system, where a ZP value of ±30 mV is considered a stable and satisfactory formulation [24,29]. Representative graphs based on an independent measurement of the zeta potential and particle size distribution are shown in Figure 1a,b.…”

“…Particle Size, Polydispersity Index, and Zeta Potential Measurement of particle size (PS) and polydispersity index (PDI) was based on the principle of dynamic light scattering using the Nano series Zetasizer (Malvern Instruments Ltd, Malvern, UK). For each quantification, RDS samples were re-dispersed in deionized water, appropriately diluted, and sonicated (Table-type Supersonic Cleaner KQ118, Nanjing T-Bota Scietech Instruments and Equipment, Co, Ltd., Nanjing, China) for 15 min at 37 ± 0.5 • C. All measurements were performed as three independent replicates with 10 readings per sample at a measurement angle of 173 • and temperature of 25 • C. Zeta potential (ZP) is an indicator of particle surface charge, which determines particle stability in dispersions [23,24]. It was computed based on the Smoluchowski equation [25]…”

“…To get an indication of the release kinetics of the RDS formulation, the pH 7.4 release profile was selected for further mathematical model fitting over an extended period when 100% drug release was achieved. Resulting data were further analyzed using the KientDS version 3.0 open source software, which aided the selection of the model of best fit, which was based on mathematical computations, such as the zero, first, and second order kinetics, Higuchi, Korsmeyer-Peppas, Michaelis-Menten and Weibull approaches [19,24,27].…”

“…The RDS powder formulation showed an average particle size of 1.63 ± 0.20 µm, indicating its intrinsic micro-structure. The PDI can be described as a ratio that provides information about homogeneity of particle size distribution as it relates to a particular system serving as a useful reflection of the quality of the particulate system/dispersion ranging from 0.0-1.0 with values ≤0.1 relating to the highest quality of particulate dispersion, ≤0.3 as optimum, ≤0.5 as generally acceptable [24]. A generally acceptable PDI value of 0.37 ± 0.04 was recorded for the RDS powder, indicating that the particles were mostly homogenous and well dispersed within the formulation.…”